Anti-cancer compounds

ABSTRACT

The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like.

[0001] The present invention relates to 2-substituted4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositionscontaining them, and their use in the treatment of proliferativedisorders such as cancer, leukemia, psoriasis and the like.

BACKGROUND TO THE INVENTION

[0002] Certain4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidineamines havinganti-asthmatic properties are disclosed in EP-A-233,461. Certain4-heteroaryl-N-(3-substituted-phenyl)-2-pyridineamines possessinganti-proliferative properties and inhibiting protein kinases C,epidermal growth factor receptor-associated tyrosine protein kinase(EGF-R-TPK), as well as CDK1/cyclin B have been disclosed in WO95/09847wherein the exemplified heteroaryl are pyridyl and indolyl.

[0003] J. Med. Chem. (1993) Vol. 36, pages 2716-2725, Paul, R. et al:discloses a further class of phenyl amino-pyrimidines possessinganti-inflammatory activity. These compounds include mono-substituted2-thienyl groups at the 4-position of the pyrimidine ring anddimethyl-3-furyl groups at this position.

[0004] It is an aim of the present invention to provide a further classof N-phenyl-2-pyrimidine anti-proliferative compounds. The compounds ofthe present invention have surprisingly been found to not to beinhibitors of protein kinase C. As discussed hereinafter, their activitymay be demonstrated by inhibition of cell proliferation in cell linesand/or inhibition of cyclin dependent kinase enzymes. Throughout thespecification, the term “thienyl” is used interchangeably with“thiophene”

SUMMARY OF THE INVENTION

[0005] The first aspect of the present invention relates to compounds ofgeneral formula I:

[0006] wherein:

[0007] X¹ is CH and X² is S; or

[0008] one of X¹ and X² is S, and the other of X¹ and X² is N;

[0009] Z is NH, NHCO, NHSO₂, NHCH₂, CH₂, CH₂CH₂, or CH═CH;

[0010] R¹, R², and R³ are independently H, alkyl, aryl, aralkyl,heterocycle, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NH—R′,N—(R′)(R″), NH—COR′, NH-aryl, N-(aryl)₂, COOH, COO—R′, COO-aryl, CONH₂,CONH—R′, CON—(R′)(R″), CONH-aryl, CON-(aryl)₂, SO₃H, SO₂NH₂, CF₃, CO—R′,or CO-aryl, wherein alkyl, aryl, aralkyl, heterocycle and NH-aryl groupsmay be further substituted with one or more groups selected fromhalogeno, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃; at least oneof the groups R¹ and R² being other than H when either X¹ or X² is S;

[0011] R⁴, R⁵, R⁶, R⁷, and R⁸ are independently from each other H,substituted or unsubstituted lower alkyl, halogeno, NO₂, CN, OH,substituted or unsubstituted alkoxy, NH₂, NH—R′, alkyl-aryl,alkyl-heteroaryl, NH(C═NH)NH₂, N(R′)₃ ⁺, N—(R′) (R″), COOH, COO—R′,CONH₂, CONH—R′, CON-(R′)(R″), SO₃H, SO₂NH₂, CF₃ or(CH₂)_(n)O(CH₂)_(m)NR′R″, (CH₂)_(n)CO₂(CH₂)_(m)OR′″ wherein n is 0, 1, 2or 3 and m is 1, 2 or 3;

[0012] wherein R′, R″ and R″′ are each independently alkyl groups thatmay be the same or different;

[0013] and pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE FIGURES

[0014]FIG. 1 shows the chemical structure of compounds 1-119 accordingto the invention.

[0015]FIG. 2 shows the mitotic arrest and induction of apoptosis bycompound 28 in Saos-2 cells. Cells were treated with 1 μM compound 28for 48 h. Mitotic and apoptotic cells are indicated by the arrows.

[0016]FIG. 3 shows the effect of compound 28 and Vinblastine on mitoticindex. FIG. 3A shows the plate plan and FIG. 3B shows the image from thescan plate window. (The plates shaded in black are “below range.” Theplates shaded in dark gray are “above range.” The plates shaded in lightgray are “in range.”)

[0017]FIG. 4 shows representative images from compound 28 treated wells.

[0018]FIG. 4A—Compound 28, 4.4 μM Hoechst stain for nuclei

[0019]FIG. 4B—Compound 28, 4.4 μM anti mitotic stain

[0020]FIG. 4C—Control cells, Hoechst stain for nuclei

[0021]FIG. 4D—Control cells, anti mitotic stain

[0022]FIG. 5 shows the effect of compound 28 on the mitotic index (%cells against concentration of compound). (The curve on the left isVinblastine.) (The curve on the right is CYC4068.)

[0023]FIG. 6 shows the induction of programmed cell death by compound28. In more detail, FIG. 6 shows human lung carcinoma cells (A549)treated for 16 h with 10 μM compound 28. Extensive cytoplasmicvaculation is observed in the treated cell (A) but not in the controlcells (B).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] As used herein the term “alkyl” includes both straight chain andbranched alkyl groups having from 1 to 8 carbon atoms, e.g. methyl,ethyl propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc.and the term “lower alkyl” is similarly used for groups having from 1 to4 carbon atoms.

[0025] The term “aryl” is used to include groups having from 6 to 10carbon atoms, e.g. phenyl, naphthyl etc.

[0026] The term “aralkyl” is used as a conjunction of the terms alkyland aryl as given above.

[0027] This invention provides a compound of general formula I:

[0028] wherein:

[0029] X¹ is CH and X² is S; or

[0030] one of X¹ and X² is S, and the other of X¹ and X² is N;

[0031] Z is NH, NHCO, NHSO₂, NHCH₂, CH₂, CH₂CH₂, or CH═CH;

[0032] R¹, R², and R³ are independently H, alkyl, aryl, aralkyl,heterocycle, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NH—R′,N—(R′)(R″), NH—COR′, NH-aryl, N-(aryl)₂, COOH, COO—R′, COO-aryl, CONH₂,CONH—R′, CON—(R′)(R″), CONH-aryl, CON-(aryl)₂, SO₃H, SO₂NH₂, CF₃, CO—R′,or CO-aryl, wherein alkyl, aryl, aralkyl, heterocycle and NH-aryl groupsmay be further substituted with one or more groups selected fromhalogeno, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃; at least oneof the groups R¹ and R² being other than H when either X¹ or X² is S;

[0033] R⁴, R⁵, R⁶, R⁷, and R⁸ are independently from each other H,substituted or unsubstituted lower alkyl, halogeno, NO₂, CN, OH,substituted or unsubstituted alkoxy, NH₂, NH—R′, alkyl-aryl,alkyl-heteroaryl, NH(C═NH)NH₂, N(R′)₃ ⁺, N—(R′) (R″), COOH, COO—R′,CONH₂, CONH—R′, CON—(R′)(R″), SO₃H, SO₂NH₂, CF₃ or(CH₂)_(n)O(CH₂)_(m)NR′R″, (CH₂)_(n)CO₂(CH₂)_(m)OR′″ wherein n is 0, 1, 2or 3 and m is 1, 2 or 3;

[0034] wherein R′, R″ and R″′ are each independently alkyl groups thatmay be the same or different;

[0035] and pharmaceutically acceptable salts thereof.

[0036] This invention further provides the above compound, wherein;

[0037] X¹ and X² are S and N respectively, or CH and S respectively;

[0038] R¹, R² and R³ are each independently selected from H, alkyl,aryl, aralkyl, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NHCOR′,NHCOR′, NH-aryl, NH—R′, N—(R′)(R″), COOH, COO—R′, CONH₂, CONH—R′,CON—(R′)(R″), SO₃H, SO₂NH₂, CF₃, and CO—R′ wherein alkyl, aryl, NH-aryland aralkyl groups may be further substituted with one or more groupsselected from halogeno, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃;

[0039] Z is selected from N, NHSO₂ and NHCH₂;

[0040] R⁴-R⁸ are each independently selected from H, OH, halogeno,nitro, amino, alkoxy, carbamoyl, sulfamyl, C₁₋₄ alkyl, substituted C₁₋₄alkyl, COOH, COOR′, CN, CF₃, (CH₂)_(n)O(CH₂)_(m)NR′R″, alkyl-aryl,alkyl-heteroaryl, NH(C═NH)NH₂, N(R′)₃ ⁺, N(R′)(R″) and(CH₂)_(n)CO₂(CH₂)_(m)OR′″.

[0041] In an embodiment of the above compounds, X¹ and X² are S and Nrespectively.

[0042] In another embodiment of the above compounds, Z is NH and R³ isH.

[0043] Included within the scope of this invention are the abovecompounds, wherein R¹ and R² are each independently one or more ofhalogeno, a C₁₋₄ alkyl group, H, aryl, heterocycle or NH(R′).

[0044] In an embodiment of the above compounds, R¹ and R² are bothchloro or methyl.

[0045] In another embodiment of the above compounds, R³ is selected fromH, aryl, substituted aryl, halo, C₁₋₄ alkoxy and OH.

[0046] This invention includes the above compounds wherein R⁴ to R⁸ areselected independently from F, NH₂, NO₂, OH, Cl, Br, I, CF₃, OMe, COOH,COOR′, CN, H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂CO₂CH₂CH₂OMe, NH(C═NH)NH₂, andCO₂CH₂CH₂OMe, CH₂OCH₂CH₂NEt₂, CH₂-heteroaryl, NMe₃ ⁺, NMe₂.

[0047] This invention features a compound selected from;

[0048] (a) 2-{N-(phenyl)}-4-(2,4-dimethylthiazol-5-yl)pyrimidineaminesin which the phenyl group is 2-, 3- or 4-substituted by at least one ofMe, F, NH₂, NO₂, OH, Cl, Br, I, CF₃, OMe, CN, COOH, CH₂OH, COOMe, COOEt,NH(C═NH)NH₂, CH₂CO₂CH₂CH OMe, CH₂-pyridyl, CH₂OCH₂CH₂NEt₂, CO₂CH₂CH₂OMe,NMe₃ ⁺ and NMe₂;

[0049] (b) 2-{N-(phenyl)}-4-(2,5-dichloro-thien-3-yl)pyrimidineamines inwhich the phenyl group is 2-, 3- or 4-substituted by at least one of F,NO₂, OH, Cl, or OMe;

[0050] (c) 2-{N-(phenyl)}-4-(2,5-dimethyl-thien-3-yl)pyrimidineamines inwhich the phenyl group is 2-, 3- or 4-substituted by at least one of F,NO₂, OH, Cl, or OMe, and

[0051] (d)2-{N-(phenyl)}-4-(4-methyl-2-methylamino-thiazol-5-yl)pyrimidineaminesin which the phenyl group is 2-, 3- or 4-substituted by at least one ofF, OH, I, NO₂, Cl, COOR′, Br, OMe or CF₃.

[0052] This invention features the above compounds, wherein;

[0053] for group (a) the phenyl group is mono-substituted by F, NH₂,NO₂, OH, Cl, Br, I, CF₃, OMe, CN, CH₂OH, COOH, COOMe, COOEt,CH₂CO₂CH₂CH₂OMe or CO₂CH₂CH₂OMe at any of the 2,3 or 4-positions, ordi-substituted by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro,2,4-dichloro, 3,5-dichloro, 3,4-dichloro, 4-hydroxy-2-nitro,4-hydroxy-3-nitro, 6-chloro-3-carboxy, 4-chloro-3-carboxy,6-chloro-2-carboxy, 2-fluoro-4-iodo, 2-hydroxy-4-methoxy,3-chloro-4-iodo, 3-chloro-4-hydroxy, 3-chloro-4-methyl,3-chloro-4-methoxy, 4-fluoro-3-nitro, 6-chloro-3-methoxycarbonyl,3-chloro-4-methoxcarbonyl, 3-chloro-4-ethoxcarbonyl,2-hydroxy-4-methoxy, 2-chloro-5-methoxycarbonyl,4-chloro-3-methoxycarbonyl, 6-chloro-3-(CO₂CH₂CH₂OMe),3-chloro-4-(CO₂CH₂CH₂OMe), 4-chloro-3-trifluoromethyl, or3-(CO₂CH₂CH₂OMe)-4-fluoro.

[0054] for group (b) the phenyl group is mono-substituted by chloro, or,nitro, at any of the 2, 3 or 4-positions;

[0055] for group (c) the phenyl group is mono-substituted by chloro atany of the 2, 3 or 4-positions,

[0056] for group (d) the phenyl group is mono-substituted by chloro,bromo, iodo, fluoro, OH, nitro, CF₃ or OMe at any of the 2, 3 or 4positions, or disubstituted by 4-hydroxy-3-nitro,3-chloro-4-ethoxycarbonyl, 3,4-difluoro, 2,4-difluoro,4-chloro-3-trifluoromethyl or 4-fluoro-3-nitro.

[0057] In an embodiment of the above compounds, for group (a) the phenylgroup is monosubstituted by Br, I or CF₃.

[0058] This invention also features one or more compounds selected from;

[0059] 4-(2,5-Dichloro-thiophen-3-yl)-2-phenyl-pyrimidine,

[0060](2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0061](4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0062](3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0063](2-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0064](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0065](3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0066]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,

[0067]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0068]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0069]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,

[0070]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0071]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0072](4-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0073](2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0074](3-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0075]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,

[0076]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0077](2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0078](3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0079](3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0080](2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0081]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0082]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,

[0083]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0084](2-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0085](3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine

[0086](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0087]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0088]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,

[0089]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,

[0090]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-pyridin-2-yl-amine,

[0091]{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-(3-fluoro-phenyl)-amine,

[0092](3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0093]{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,

[0094]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,

[0095]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,

[0096] 3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0097] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0098]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,

[0099]4-Chloro-N-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzenesulfonamide,

[0100]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-fluoro-benzenesulfonamide,

[0101]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0102]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-nitro-benzenesulfonamide,

[0103]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,

[0104]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0105]3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0106] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0107](3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0108](3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0109] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0110]{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0111]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0112]4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-ylamino}-phenol,

[0113](3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0114]4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0115]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0116](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0117]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0118]{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0119](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,

[0120]4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0121](4-Fluoro-phenyl)-{4-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0122]{4-(2,4-Dimethyl-thiazol-5-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0123]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,

[0124]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl)-phenol,

[0125]{4-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0126](4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0127]4-{2-Amino-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,

[0128]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0129]2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0130]{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0131]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0132]3-{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0133]2-Chloro-4-{4-(2-ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0134]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,

[0135]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,

[0136]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0137] 2-Chloro-5-{3-(2,4-dimethyl-thiazol-5-yl)-phenylamino}-benzoicacid,

[0138]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl)}-(4-fluoro-phenyl)-amine,

[0139](3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0140]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0141]3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0142](4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0143](4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0144](3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0145]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0146]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0147]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0148]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0149]3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0150]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,

[0151]2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,

[0152](3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0153]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0154]5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,

[0155]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0156]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0157]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0158](3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0159](3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0160](3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0161](2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0162](3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0163](4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0164](3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0165](4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0166](4-Fluoro-3-nitro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0167]4-{4-{2-(4-Nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-ylamino}-phenol,

[0168]N-{5-{2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl}-4-methyl-thiazol-2-yl}-acetamide,

[0169](4-Fluoro-phenyl)-{4-{2-(4-nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-yl}-amine,

[0170] 4-{4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0171]N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,

[0172]{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-methanol,

[0173]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,

[0174]{3-(2-Diethylamino-ethoxymethyl)-phenyl}-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0175]N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,and

[0176]{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.

[0177] Also encompassed by this invention are one or more compoundsselected from the following:

[0178](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0179](3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0180]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0181]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0182]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0183]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,

[0184]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0185](2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0186](3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0187]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0188](3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0189](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0190]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,

[0191]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0192](3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0193]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,

[0194]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,

[0195]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,

[0196] 3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0197] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0198]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0199]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,

[0200]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0201]3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0202] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0203](3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0204](3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0205] 4-{-4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0206]{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0207]4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0208](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0209]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0210](4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0211]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0212]2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0213]{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0214]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0215]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0216](3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0217]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0218]3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0219](4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0220](4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0221](3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0222]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0223]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0224]5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,

[0225]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0226](3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0227](4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0228](3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0229](4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0230]2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,

[0231](3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0232](3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0233]N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,

[0234]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,

[0235]N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,

[0236]{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.

[0237] In addition, this invention provides a compound selected from thefollowing:

[0238]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0239](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0240]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0241](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.

[0242] Further, this invention provides one or more compounds selectedfrom the following:

[0243](2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0244](4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0245](3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0246](2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0247](3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0248](2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0249]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0250]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,

[0251]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine,

[0252]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,

[0253]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,

[0254]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0255](3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0256](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,

[0257]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,

[0258]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol,

[0259]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0260]3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0261]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,

[0262](3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0263]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0264](3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0265](2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.

[0266] This invention includes the compound{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine.

[0267] In one aspect, this invention pertains to pharmaceuticalcompositions comprising a compound as described above or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable excipient.

[0268] This invention also pertains to the above pharmaceuticalcompositions which further comprise one or more other anticancer agents.

[0269] This invention includes the use of one or more of theabove-described compounds or pharmaceutically acceptable salts thereofin the treatment of a proliferative disorder.

[0270] In an embodiment of the above use, the proliferative disorder iscancer or leukaemia.

[0271] In another embodiment of the above uses, said one or morecompounds are administered in an amount sufficient to inhibit at leastone CDK enzyme.

[0272] In still another embodiment of the above uses, the CDK enzyme isCDK2 and/or CDK4.

[0273] In another aspect, this invention provides the use of one or morecompounds of formula

[0274] wherein:

[0275] X¹ is CH and X² is S; or

[0276] one of X¹ and X² is S, and the other of X¹ and X² is N;

[0277] Z is NH, NHCO, NHSO₂, NHCH₂, CH₂, CH₂CH₂, or CH═CH;

[0278] R¹, R², and R³ are independently H, alkyl, aryl, aralkyl,heterocycle, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NH—R′,N—(R′)(R″), NH-aryl, N-(aryl)₂, COOH, COO—R′, COO-aryl, CONH₂, CONH—R′,CON—(R′)(R″), CONH-aryl, CON-(aryl)₂, SO₃H, SO₂NH₂, CF₃, CO—R′, orCO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups may befurther substituted with one or more groups selected from halogeno, NO₂,CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃;

[0279] R⁴, R⁵, R⁶, R⁷, and R⁸ are independently from each other H,substituted or unsubstituted lower alkyl, halogeno, NO₂, CN, OH,substituted or unsubstituted alkoxy, NH₂, NH—R′, N—(R′)(R″), COOH,COO—R′, CONH₂, CONH—R′, CON—(R′) (R″), SO₃H, SO₂NH₂, or CF₃, other thanwhen R⁵, R⁶ and R⁷ are all methoxy and R⁴ and R⁸ are hydrogen or when R⁶and R⁷ are both methoxy and R⁴, R⁵ and R⁸ are all hydrogen;

[0280] wherein R′ and R″ are each independently alkyl groups that may bethe same or different;

[0281] and pharmaceutically acceptable salts thereof;

[0282] in the manufacture of a medicament for use in the treatment of aproliferative disease.

[0283] In an embodiment of the above uses, the compound is any of theabove-described compounds.

[0284] In another embodiment of the above uses, the compound isadministered in combination with one or more other anticancer compounds.

[0285] Preferred compounds of formula I are those bearing a mono- ordi-substituted 5-membered heterocyclic radical, attached to thepyrimidine ring through one of the ring carbon atoms and chosen from thefollowing: thiazol-3-yl thiazol-5-yl and thien-3-yl, preferably athien-3-yl or thiazol-5-yl, most preferably, the heterocycle is athiazol-5-yl group.

[0286] Preferably, R¹, R² and R³ are each independently selected from H,alkyl, aryl, aralkyl, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂,NHCOR′, NHCOR′, NH-aryl, NH—R′, N—(R′)(R″), COOH, COO—R′, CONH₂,CONH—R′, CON—(R′)(R″), SO₃H, SO₂NH₂, CF₃, and CO—R′ wherein alkyl, aryl,NH-aryl and aralkyl groups may be further substituted with one or moregroups selected from halogeno, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂and CF₃;

[0287] More preferably, R^(1 and R) ² are each independently halogeno,C₁₋₄ alkyl group, H, aryl, heterocycle or NH(R′). Even more preferably,R¹ and R² are both chloro or both methyl.

[0288] R³ is preferably selected from H, aryl, substituted aryl, halo,C₁₋₄ alkoxy and OH, more preferably, R³ is H or methyl, most preferablyH.

[0289] The group Z is preferably NH, NHSO₂ or NHCH₂, more preferably NHor NHSO₂ most preferably NH.

[0290] The phenyl substituents R⁴-R⁸ are preferably selected from H, OH,halogeno, nitro, amino, alkoxy, carbamoyl, sulfamyl, C₁₋₄ alkyl,substituted C₁₋₄ alkyl, COOH, COOR′, CN, CF₃, (CH₂)_(n)O(CH₂)_(m)NR′R″,alkyl-aryl, alkyl-heteroaryl, NH(C═NH)NH₂, N(R′)₃ ⁻, N(R′)(R″) and(CH₂)_(n)CO₂(CH₂)_(m)OR′″.

[0291] Even more preferably, R⁴-R⁸ are each independently F, NH₂, NO₂,OH, Cl, Br, I, CF₃, OMe, COOH, COOR′, CN, H, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂CO₂CH₂CH₂OMe, NH(C═NH)NH₂, and CO₂CH₂CH₂OMe, CH₂OCH₂CH₂NEt₂,CH₂-heteroaryl, NMe₃ ⁺, NMe₂.

[0292] R′, R″, and R″′ are each independently preferably methyl orethyl.

[0293] Particularly preferred combinations of the above statedpreferences include where the heterocycle is a thien-3-yl group or athiazol-5-yl group, the latter being most preferred, Z being NH, R³being H and the remaining groups being selected from the preferencesstated above. Particularly preferable is when R¹ and R² are eachindependently one or more of halogeno or C₁₋₄ alkyl groups, especiallywhen R¹ and R² are both chloro or methyl and when R⁴ to R⁸ are selectedindependently from of F, NH₂, NO₂, OH, Cl, Br, I, CF₃ and OMe.

[0294] In a particularly preferred embodiment of the invention, X¹ andX² are S and N respectively.

[0295] In another particularly preferred embodiment, Z is NH and R³ isH.

[0296] Thus, particularly preferred embodiments include;

[0297] (a) 2-{N-(phenyl)}-4-(2,4-dimethylthiazol-5-yl)pyrimidineaminesin which the phenyl group is 2-, 3- or 4-substituted by at least one ofMe, F, NH₂, NO₂, OH, Cl, Br, I, CF₃, OMe, CN, COOH, CH₂OH, COOMe, COOEt,NH(C═NH)NH₂, CH₂CO₂CH₂CH₂OMe, CH₂-pyridyl, CH₂OCH₂CH₂NEt₂, CO₂CH₂CH₂OMe,NMe₃ ⁺ and NMe₂;

[0298] (b) 2-{N-(phenyl)}-4-(2,5-dichloro-thien-3-yl)pyrimidineamines inwhich the phenyl group is 2-, 3- or 4-substituted by at least one of F,NO₂, OH, Cl, or OMe;

[0299] (c) 2-{N-(phenyl)}-4-(2,5-dimethyl-thien-3-yl)pyrimidineamines inwhich the phenyl group is 2-, 3- or 4-substituted by at least one of F,NO₂, OH, Cl, or OMe, and

[0300] (d)2-{N-(phenyl)}-4-(4-methyl-2-methylamino-thiazol-5-yl)pyrimidineaminesin which the phenyl group is 2-, 3- or 4-substituted by at least one ofF, OH, I, NO₂, Cl, COOR′, Br, OMe or CF₃.

[0301] Within these groups (a) to (d), the following phenyl substituentsare preferable;

[0302] for group (a) the phenyl group is mono-substituted by F, NH₂,NO₂, OH, Cl, Br, I, CF₃, OMe, CN, CH₂OH, COOH, COOMe, COOEt,CH₂CO₂CH₂CH₂OMe or CO₂CH₂CH₂OMe at any of the 2, 3 or 4-positions, ordi-substituted by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro,2,4-dichloro, 3,5-dichloro, 3,4-dichloro, 4-hydroxy-2-nitro,4-hydroxy-3-nitro, 6-chloro-3-carboxy, 4-chloro-3-carboxy,6-chloro-2-carboxy, 2-fluoro-4-iodo, 2-hydroxy-4-methoxy,3-chloro-4-iodo, 3-chloro-4-hydroxy, 3-chloro-4-methyl,3-chloro-4-methoxy, 4-fluoro-3-nitro, 6-chloro-3-methoxycarbonyl,3-chloro-4-methoxcarbonyl, 3-chloro-4-ethoxcarbonyl,2-hydroxy-4-methoxy, 2-chloro-5-methoxycarbonyl,4-chloro-3-methoxycarbonyl, 6-chloro-3-(CO₂CH₂CH₂OMe),3-chloro-4-(CO₂CH₂CH₂OMe), 4-chloro-3-trifluoromethyl, or3-(CO₂CH₂CH₂OMe)-4-fluoro.

[0303] for group (b) the phenyl group is mono-substituted by chloro, or,nitro, at any of the 2, 3 or 4-positions;

[0304] for group (c) the phenyl group is mono-substituted by chloro atany of the 2, 3 or 4-positions,

[0305] for group (d) the phenyl group is mono-substituted by chloro,bromo, iodo, fluoro, OH, nitro, CF₃ or OMe at any of the 2, 3 or 4positions, or disubstituted by 4-hydroxy-3-nitro,3-chloro-4-ethoxycarbonyl, 3,4-difluoro, 2,4-difluoro,4-chloro-3-trifluoromethyl or 4-fluoro-3-nitro.

[0306] Even more preferably, for group (a) the phenyl group ismonosubstituted by Br, I or CF₃.

[0307] Most preferably, the compounds of the present invention areselected from;

[0308] 4-(2,5-Dichloro-thiophen-3-yl)-2-phenyl-pyrimidine,

[0309](2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0310](4-Chloro-phenyl)-4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0311](3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0312](2-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0313](4-Chloro-phenyl)-{4-(2,4-dimethylthiazol-5-yl)-pyrimidin-2-yl}-amine,

[0314](3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0315]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,

[0316]{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0317]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,

[0318]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0319]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0320]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0321](4-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0322](2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0323](3-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0324]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,

[0325]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0326](2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0327](3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0328](3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0329](2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0330]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0331]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,

[0332]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0333](2-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0334](3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0335](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0336]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine,

[0337]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,

[0338]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,

[0339]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-pyridin-2-yl-amine,

[0340]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine,

[0341](3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0342]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,

[0343]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,

[0344]{4-(2,4-Dimethylthiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,

[0345] 3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0346] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0347]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,

[0348]4-Chloro-N-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzenesulfonamide,

[0349]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-fluoro-benzenesulfonamide,

[0350]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0351]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-nitro-benzenesulfonamide,

[0352]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,

[0353]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0354]3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0355] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0356](3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0357](3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0358] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0359]{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0360]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0361]4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-ylamino}-phenol,

[0362](3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0363]4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0364]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0365](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0366]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0367]{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0368](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,

[0369]4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0370](4-Fluoro-phenyl)-{4-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0371]{4-(2,4-Dimethyl-thiazol-5-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0372]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,

[0373]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol,

[0374]{4-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0375](4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0376]4-{2-Amino-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,

[0377]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0378]2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0379]{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0380]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0381]3-{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0382]2-Chloro-4-{4-(2-ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0383]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,

[0384]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,

[0385]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0386] 2-Chloro-5-{3-(2,4-dimethyl-thiazol-5-yl)-phenylamino}-benzoicacid,

[0387]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0388](3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0389]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0390]3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0391](4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0392](4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0393](3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0394]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0395]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0396]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0397]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0398]3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0399]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,

[0400]2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,

[0401](3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0402]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0403]5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,

[0404]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0405]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0406]2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0407](3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0408](3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0409](3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0410](2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0411](3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0412](4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0413](3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0414](4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0415](4-Fluoro-3-nitro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0416]4-{4-{2-(4-Nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-ylamino}-phenol,

[0417]N-{5-{2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl}-4-methyl-thiazol-2-yl}-acetamide,

[0418](4-Fluoro-phenyl)-{4-{2-(4-nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-yl}-amine,

[0419] 4-{4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0420]N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,

[0421]{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-methanol,

[0422]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,

[0423]{3-(2-Diethylamino-ethoxymethyl)-phenyl}-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0424]N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,

[0425]{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.

[0426] The structures of the above-mentioned compounds are illustratedin FIG. 1.

[0427] Particularly preferred compounds observed to be CDK inhibitorsinclude the following:

[0428](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0429](3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0430] {4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0431]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0432]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,

[0433]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,

[0434]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0435](2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0436](3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0437]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0438](3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0439](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0440]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,

[0441]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine,

[0442](3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0443]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,

[0444]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,

[0445]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,

[0446] 3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0447] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0448]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0449]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,

[0450]4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0451]3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,

[0452] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0453](3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0454](3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0455] 4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid,

[0456]{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0457]4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0458](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0459]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0460](4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0461]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,

[0462]2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0463]{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0464]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0465]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,

[0466](3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0467]{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0468]3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0469](4-Bromo-phenyl)-4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0470](4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0471](3-Methoxy-phenyl)-4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0472]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0473]{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0474]5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,

[0475]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0476](3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0477](4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0478](3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0479](4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0480]2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,

[0481](3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0482](3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0483]N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,

[0484]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,

[0485]N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,

[0486]{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.

[0487] Even more preferred compounds observed to be CDK inhibitorsinclude the following:

[0488]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,

[0489](4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0490]4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,

[0491](4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.

[0492] The following compounds are observed to be particularly effectiveanti-proliferative agents, as demonstrated by cell-based assays:

[0493](2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0494](4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0495](3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0496](2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,

[0497](3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0498](2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0499]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,

[0500]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,

[0501]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine,

[0502]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,

[0503]N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,

[0504]{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,

[0505](3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0506](4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,

[0507]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl-2,6-dimethoxy-phenol,

[0508]4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol,

[0509]2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0510]3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,

[0511]{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,

[0512](3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,

[0513]4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,

[0514](3-Iodo-phenyl)-{4-(4-methyl-2-methylaminothiazol-5-yl)-pyrimidin-2-yl}-amine,

[0515](2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.

[0516] The following compound is observed to be an even more effectiveanti-proliferative agent, as demonstrated by cell-based assays:{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine.

[0517] The compounds of formula I have been found to possessanti-proliferative activity and are therefore believed to be of use inthe treatment of proliferative disorders such as cancers, leukaemias andother disorders associated with uncontrolled cellular proliferation suchas psoriasis and restenosis. As defined herein, an anti-proliferativeeffect within the scope of the present invention may be demonstrated bythe ability to inhibit cell proliferation in an in vitro whole cellassay, for example using any of the cell lines A549, HT29, Saos-2, HeLaor MCF-7, or by showing inhibition of a CDK enzyme (such as CDK2 orCDK4) in an appropriate assay. These assays including methods for theirperformance are described in more detail in Example 23. Using such cellline and enzymes assays it may be determined whether a compound isanti-proliferative in the context of the present invention.

[0518] Without wishing to be bound by theory, the compounds of thepresent invention are believed to exert their anti-proliferative effectin a non-protein kinase C (PKC) dependent manner. Many of the compoundsinhibit cyclin-dependent kinase enzymes (CDKs) that have been shown tobe involved in cell cycle control. These CDKs include CDK2 and CDK4 andparticularly their respective interactions with cyclin E and cyclin D1.These compounds of the present invention are further believed to beadvantageous in being selective for CDK enzymes implicated inproliferative diseases. By the term “selective” it is meant thatalthough possible having some inhibitory effect on another enzyme (suchas PKC), the compound is preferentially effective against an enzymeimplicated in proliferative diseases.

[0519] The compounds of the invention may inhibit any of the steps orstages in the cell cycle, for example, formation of the nuclearenvelope, exit from the quiescent phase of the cell cycle (G0), G1progression, chromosome decondensation, nuclear envelope breakdown,START, initiation of DNA replication, progression of DNA replication,termination of DNA replication, centrosome duplication, G2 progression,activation of mitotic or meiotic functions, chromosome condensation,centrosome separation, microtubule nucleation, spindle formation andfunction, interactions with microtubule motor proteins, chromatidseparation and segregation, inactivation of mitotic functions, formationof contractile ring, and cytokinesis functions. In particular, thecompounds of the invention may influence certain gene functions such aschromatin binding, formation of replication complexes, replicationlicensing, phosphorylation or other secondary modification activity,proteolytic degradation, microtubule binding, actin binding, septinbinding, microtubule organising centre nucleation activity and bindingto components of cell cycle signalling pathways.

[0520] A further embodiment of the present invention therefore relatesto the use of one or more compounds of formula I in the treatment ofproliferative disorders. Preferably, the proliferative disorder is acancer or leukaemia. The term proliferative disorder is used herein in abroad sense to include any disorder that requires control of the cellcycle, for example cardiovascular disorders such as restenosis andcardiomyopathy, auto-immune disorders such as glomerulonephritis andrheumatoid arthritis, dermatological disorders such as psoriasis,anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria,emphysema and alopecia. In these disorders, the compounds of the presentinvention may induce apoptosis or maintain stasis within the desiredcells as required.

[0521] In a particularly preferred embodiment, the invention relates tothe use of one or more compounds of formula I in the treatment of a CDKdependent or sensitive disorder. CDK dependent disorders are associatedwith an above normal level of activity of one or more CDK enzymes. Suchdisorders preferably associated with an abnormal level of activity ofCDK2 and/or CDK4. A CDK sensitive disorder is a disorder in which anaberration in the CDK level is not the primary cause, but is downstreamof the primary metabolic aberration. In such scenarios, CDK2 and/or CDK4can be said to be part of the sensitive metabolic pathway and CDKinhibitors may therefore be active in treating such disorders. Suchdisorders are preferably cancer or leukaemic disorders.

[0522] A second aspect of the present invention relates to the use ofone or more compounds of formula

[0523] wherein:

[0524] X¹ is CH and X² is S; or

[0525] one of X¹ and X² is S, and the other of X¹ and X² is N;

[0526] Z is NH, NHCO, NHSO₂, NHCH₂, CH₂, CH₂CH₂, or CH═CH;

[0527] R¹, R², and R³ are independently H, alkyl, aryl, aralkyl,heterocycle, halogeno, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NH—R′,N—(R′)(R″), NH-aryl, N-(aryl)₂, COOH, COO—R′, COO-aryl, CONH₂, CONH—R′,CON—(R′)(R″), CONH-aryl, CON-(aryl)₂, SO₃H, SO₂NH₂, CF₃, CO—R′, orCO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups may befurther substituted with one or more groups selected from halogeno, NO₂,CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃;

[0528] R⁴, R⁵, R⁶, R⁷, and R⁸ are independently from each other H,substituted or unsubstituted lower alkyl, halogeno, NO₂, CN, OH,substituted or unsubstituted alkoxy, NH₂, NH—R′, N—(R′)(R″), COOH,COO—R′, CONH₂, CONH—R′, CON—(R′) (R″), SO₃H, SO₂NH₂, or CF₃, other thanwhen R⁵, R⁶ and R⁷ are all methoxy and R⁴ and R⁸ are hydrogen or when R⁶and R⁷ are both methoxy and R⁴, R⁵ and R⁸ are all hydrogen;

[0529] wherein R′ and R″ are each independently alkyl groups that may bethe same or different;

[0530] and pharmaceutically acceptable salts thereof;

[0531] in the manufacture of a medicament for use in the treatment of aproliferative disease.

[0532] The term “proliferative disorder” has been previously discussedand the same definition applies to the second aspect of the invention.

[0533] The preferred embodiments of this further aspect of the inventionare identical to those described above in respect of the first aspect.

[0534] In a particularly preferred embodiment, the one or more compoundsof the invention are administered in combination with one or more otheranticancer agents. In such cases, the compounds of the invention may beadministered consecutively, simultaneously or sequentially with the oneor more other anticancer agents.

[0535] As used herein the phrase “manufacture of a medicament” includesthe use of a compound of formula I directly as the medicament inaddition to its use in a screening programme for furtheranti-proliferative agents or in any stage of the manufacture of such amedicament.

[0536] The compounds of the present invention (first and secondsaspects) can be present as salts or esters, in particularpharmaceutically acceptable salts or esters.

[0537] Pharmaceutically acceptable salts of the compounds of theinvention (first and seconds aspects) include suitable acid addition orbase salts thereof. A review of suitable pharmaceutical salts may befound in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed,for example with strong inorganic acids such as mineral acids, e.g.sulphuric acid, phosphoric acid or hydrohalic acids; with strong organiccarboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atomswhich are unsubstituted or substituted (e.g., by halogen), such asacetic acid; with saturated or unsaturated dicarboxylic acids, forexample oxalic, malonic, succinic, maleic, fumaric, phthalic ortetraphthalic; with hydroxycarboxylic acids, for example ascorbic,glycolic, lactic, malic, tartaric or citric acid; with aminoacids, forexample aspartic or glutamic acid; with benzoic acid; or with organicsulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonic acids which areunsubstituted or substituted (for example, by a halogen) such asmethane- or p-toluene sulfonic acid.

[0538] Esters are formed either using organic acids oralcohols/hydroxides, depending on the functional group being esterified.Organic acids include carboxylic acids, such as alkanecarboxylic acidsof 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., byhalogen), such as acetic acid; with saturated or unsaturateddicarboxylic acid, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, forexample ascorbic, glycolic, lactic, malic, tartaric or citric acid; withaminoacids, for example aspartic or glutamic acid; with benzoic acid; orwith organic sulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonicacids which are unsubstituted or substituted (for example, by a halogen)such as methane- or p-toluene sulfonic acid. Suitable hydroxides includeinorganic hydroxides, such as sodium hydroxide, potassium hydroxide,calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcoholsof 1-12 carbon atoms which may be unsubstituted or substituted, e.g. bya halogen).

[0539] In all aspects of the present invention previously discussed, theinvention includes, where appropriate all enantiomers and tautomers ofcompounds of formula I. The man skilled in the art will recognisecompounds that possess an optical properties (one or more chiral carbonatoms) or tautomeric characteristics. The corresponding enantiomersand/or tautomers may be isolated/prepared by methods known in the art.

[0540] The invention furthermore relates to the compounds of or of usein the present invention (first and seconds aspects) in their variouscrystalline forms, polymorphic forms and (an)hydrous forms. It is wellestablished within the pharmaceutical industry that chemical compoundsmay be isolated in any of such forms by slightly varying the method ofpurification and or isolation form the solvents used in the syntheticpreparation of such compounds.

[0541] The invention further includes the compounds (first and secondsaspects) of or of use in the present invention in prodrug form. Suchprodrugs are generally compounds of formula I wherein one or moreappropriate groups have been modified such that the modification may bereversed upon administration to a human or mammalian subject. Suchreversion is usually performed by an enzyme naturally present in suchsubject, though it is possible for a second agent to be administeredtogether with such a prodrug in order to perform the reversion in vivo.Examples of such modifications include ester (for example, any of thosedescribed above), wherein the reversion may be carried out be anesterase etc. Other such systems will be well known to those skilled inthe art.

[0542] The present invention also encompasses pharmaceuticalcompositions comprising the compounds of the invention (first andseconds aspects). In this regard, and in particular for human therapy,even though the compounds of the present invention (including theirpharmaceutically acceptable salts, esters and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutical carrier, excipient ordiluent selected with regard to the intended route of administration andstandard pharmaceutical practice.

[0543] Thus, the present invention also relates to pharmaceuticalcompositions comprising one or more compounds of formula I orpharmaceutically acceptable salts or esters thereof, together with atleast one pharmaceutically acceptable excipient, diluent or carrier.

[0544] By way of example, in the pharmaceutical compositions of thepresent invention, the compounds of the invention may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), and/or solubilising agent(s). Examples of such suitableexcipients for the various different forms of pharmaceuticalcompositions described herein may be found in the “Handbook ofPharmaceutical Excipients, 2^(nd) Edition, (1994), Edited by A Wade andPJ Weller.

[0545] The pharmaceutical compositions of the present invention may beadapted for oral, rectal, vaginal, parenteral, intramuscular,intraperitoneal, intraarterial, intrathecal, intrabronchial,subcutaneous, intradermal, intravenous, nasal, buccal or sublingualroutes of administration.

[0546] For oral administration, particular use is made of compressedtablets, pills, tablets, gellules, drops, and capsules. Preferably,these compositions contain from 1 to 250 mg and more preferably from10-100 mg, of active ingredient per dose.

[0547] Other forms of administration comprise solutions or emulsionswhich may be injected intravenously, intraarterially, intrathecally,subcutaneously, intradermally, intraperitoneally or intramuscularly, andwhich are prepared from sterile or sterilisable solutions. Thepharmaceutical compositions of the present invention may also be in formof suppositories, pessaries, suspensions, emulsions, lotions, ointments,creams, gels, sprays, solutions or dusting powders.

[0548] An alternative means of transdermal administration is by use of askin patch. For example, the active ingredient can be incorporated intoa cream consisting of an aqueous emulsion of polyethylene glycols orliquid paraffin. The active ingredient can also be incorporated, at aconcentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

[0549] Injectable forms may contain between 10-1000 mg, preferablybetween 10-250 mg, of active ingredient per dose.

[0550] Compositions may be formulated in unit dosage form, i.e., in theform of discrete portions containing a unit dose, or a multiple orsub-unit of a unit dose.

[0551] A person of ordinary skill in the art can easily determine anappropriate dose of one of the instant compositions to administer to asubject without undue experimentation. Typically, a physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will vary with the age, weight and response ofthe particular patient. The dosages disclosed herein are exemplary ofthe average case. There can of course be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention.

[0552] In an exemplary embodiment, one or more doses of 10 to 150 mg/daywill be administered to the patient for the treatment of malignancy.

[0553] The pharmaceutical compositions of the invention may furthercomprise one or more additional anticancer agents, for example, existinganticancer drugs available on the market.

[0554] Anticancer drugs in general are more effective when used incombination. In particular, combination therapy is desirable in order toavoid an overlap of major toxicities, mechanism of action and resistancemechanism(s). Furthermore, it is also desirable to administer most drugsat their maximum tolerated doses with minimum time intervals betweensuch doses. The major advantages of combining chemotherapeutic drugs arethat it may promote additive or possible synergistic effects throughbiochemical interactions and also may decrease the emergence ofresistance in early tumor cells which would have been otherwiseresponsive to initial chemotherapy with a single agent. An example ofthe use of biochemical interactions in selecting drug combinations isdemonstrated by the administration of leucovorin to increase the bindingof an active intracellular metabolite of 5-fluorouracil to its target,thymidylate synthase, thus increasing its cytotoxic effects.

[0555] Numerous combinations are used in current treatments of cancerand leukemia. A more extensive review of medical practices may be foundin “Oncologic Therapies” edited by E. E. Vokes and H. M. Golomb,published by Springer.

[0556] Beneficial combinations may be suggested by studying the growthinhibitory activity of the test compounds with agents known or suspectedof being valuable in the treatment of a particular cancer initially orcell lines derived from that cancer. This procedure can also be used todetermine the order of administration of the agents, i.e. before,simultaneously, or after delivery. Such scheduling may be a feature ofall the cycle acting agents identified herein.

[0557] Suitable anti-proliferative agents or anticancer agents that maybe used in combination with at least one compound of the presentinvention include: DNA damaging agents, anti-metabolites, anti-tumourantibiotics, natural products and their analogues, dihydrofolatereductase inhibitors, pyrimidine analogues, purine analogues,cyclin-dependent kinase inhibitors, thymidylate synthase inhibitors, DNAintercalators, DNA cleavers, topoisomerase inhibitors, anthracyclines,vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, pteridinedrugs, diynenes, podophyllotoxins, platinum containing drugs,differentiation inducers, and taxanes. Particularly useful members ofthose classes include, for example, methotrexate, methopterin,dichloromethotrexate, 5-fluorouracil, 6-mercaptopurine, tri-substitutedpurines such as olomoucine, roscovitine, bohemine and purvalanol,flavopiridol, staurosporin, cytosine arabinoside, melphalan, leurosine,actinomycin, daunorubicin, doxorubicin, mitomycin D, mitomycin A,caminomycin, aminopterin, tallysomycin, podophyllotoxin (and derivativesthereof), etoposide, cisplatin, carboplatinum, vinblastine, vincristine,vindesin, paclitaxel, docetaxel, taxotere retinoic acid, butyric acid,acetyl spermidine, tamoxifen, irinotecan and camptothecin. Mostpreferably the drug moiety is selected from methotrexate,podophyllotoxin (and derivatives thereof), etoposide, camptothecin,paclitaxel, doxorubicin, roscovitine and bohemine.

[0558] The compounds of this invention (I) can be synthesised, forexample, by an adaptation of the Traube synthesis (A. R. Katritzky, I.Taher, Can. J. Chem. 1986, 64, 2087 and references cited therein), i.e.by condensation between 1,3-dicarbonyl compounds 1 or acrylates 2 or 3,and amidine 4, as shown in Scheme 1.

[0559] The dicarbonyl compounds 1 in turn can be prepared by manymethods known in the art (J. March, In: Advanced Organic Chemistry:Reactions, Mechanism, and Structure, 4^(th) Ed., John Wiley & Sons,Inc., New York, 1992, p. 1283). Acrylates 2 and 3, which areparticularly suitable for the purposes of this invention, are obtainedfrom heterocyclic methyl ketones 5 by condensation withdimethylformamide dimethylacetal 6 and aldehydes 7 respectively, (Scheme2).

[0560] The diamino compounds 4 will be amidines 4 a or guanidines 4 b,depending on the definition of Z in general structure I. Amidines(HN═CRNH₂) can be obtained from readily available amine precursors bycondensation with e.g. ketenimines, or by addition of ammonia tosuitable nitriles or imidates. Guanidines 4 b (Scheme 3) can beelaborated by a number of methods known in the art. For the purposes ofthis invention, the most useful route is amination of cyanamide 8 withanilines 9.

[0561] Alternatively, compounds of general structure I can be obtainedfrom suitable pyrimidine precursors directly, e.g. from2,4-disubstituted (halogen, amine, etc.) pyrimidines by successivesubstitution reactions.

EXAMPLES

[0562] Abbreviations

[0563] DE MALDI-TOF MS, delayed extraction matrix assisted laserdesorption ionisation time-of-flight mass spectrometry; DMF,N,N-dimethylformamide; LC-MS, liquid chromatography-mass spectrometry;NMR, nuclear magnetic resonance spectroscopy; RP-HPLC, reversed-phasehigh performance liquid chromatography; r.t. room temperature; PE,petroleum ether (40-60° C. boiling fraction); DMSO, dimethylsulfoxide.

[0564] General

[0565] NMR spectra were recorded using a Bruker DPX-300 instrument.Chemical shifts are reported in ppm (δ) from tetramethylsilane. EMKieselgel 60 (0.040-0.063 mm) was used for flash column chromatography.Melting points were determined with a LEICA testo-720 electrothermometerand are uncorrected. Compound numbers are shown in brackets, whereappropriate.

Example 1 3-Dimethylamino-1-(2,5-dimethyl-thiophen-3-yl)-propenone

[0566] A solution of 3-acetyl-2,5-dimethylthiophene (0.1 mol, 15.4 g) inN,N-dimethylformamide dimethylacetal (14.6 mL) was refluxed under N₂ for16 h. The reaction mixture was evaporated to dryness. The residue wastriturated with iPr₂O, the resulting solid was filtered and washed withthe same solvent twice to afford the title compound as a yellow solid(8.60 g, 41%). ¹H-NMR (300 MHz, CDCl₃) δ2.40 (s, 6H, CH₃), 2.63 (s, 6H,CH₃), 5.42 (d, 1H, J=12.5 Hz, CH) 6.89 (s, 1H, Ar-H), 7.66 (d, 1H,J=12.5 Hz, CH).

4-(2,5-Dimethyl-thiophen-3-yl)-pyrimidin-2-ylamine

[0567] A mixture of3-dimethylamino-1-(2,5-dimethyl-thiophen-3-yl)-propenone (3.5 mmol,0.733 g) and guanidine carbonate (3.5 mmol, 0.631 g) in 2-methoxyethanolwas refluxed under N₂ for 21 h. The solvent was evaporated to drynessand the residue was purified by flash chromatography, using EtOAc/PE(5:1, v/v) to elute the product, which was then recrystallised fromacetone to afford the title compound as light-yellow crystals (331 mg,46%). ¹H-NMR (300 MHz, CDCl₃) a 2.43 (s, 3H, CH₃), 2.64 (s, 3H, CH₃),5.05 (br, 2H, NH₂), 6.74 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 6.97 (s, 1H,thienyl-H), 8.28 (d, 1H, J=5.2 Hz, pyrimidinyl-H).

Example 2 N-(4-Chloro-phenyl)-guanidine nitrate

[0568] A solution of 4-chloroaniline (70 mmol, 8.88 g) in EtOH (5 mL) onan ice bath was treated with nitric acid (69% aq soln.; 5 mL). To thismixture cyanamide (50% aq. soln.; 5.4 mL) was added. The reactionmixture was stirred at r.t. for 10 min and then refluxed under N₂ for afurther 22 h. The solvent was evaporated. The dark brown solid residuewas washed with EtOH and was dried under high vacuum to afford the titlecompound as a white powder (7.16 g, 44%). ¹H-NMR (300 MHz, d₆-DMSO)δ7.27-7.54 (m, 4H, Ph-H), 9.65 (br. s, 2H, NH).

(4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine{3}

[0569] A mixture of1-(2,5-dichloro-thiophen-3-yl)-3-dimethylamino-propenone (1.2 mmol, 0.29g) and N-(4-chloro-phenyl)-guanidine nitrate (1.2 mmol, 0.27 g) in iPrOH(5 mL) was treated with NaOH (48 mg). The reaction mixture was refluxedunder N₂ for 20 h. The solvent was evaporated and the residue waspurified by flash chromatography (EtOAc/PE, 5:1 and 10:3) to afford thetitle compound as a light yellow solid. Recrystallisation from EtOAc/PEgave pure product (283 mg, 66%). ¹H-NMR (300 MHz, CDCl₃) δ7.30-7.35 (m,4H, Ph-H), 7.61 (m, 2H, Ph-H), 8.48 (d, 1H, J=5.2 Hz, pyrimidyl-H).

[0570] The following compounds were prepared in a manner analogous tothat described above:

(2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine{2}

[0571]¹H-NMR (300 MHz, CDCl₃) δ6.99 (m, 1H, Ph-H), 7.29-7.42 (m, 4H,Ph-H, thienyl-H, and pyrimidinyl-H), 8.53 (d, 1H, J=5.2 Hz,pyrimidinyl-H), 8.57 (m, 1H, Ph-H).

(3-Chloro-phenyl)-{4-(4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine{4}

[0572]¹H-NMR (300 MHz, CDCl₃) δ7.02 (m, 1H, Ph-H), 7.23-7.40 (m, 4H,Ph-H, thienyl-H and pyrimidinyl-H), 7.93 (t, 1H, J=1.99, 3.95 Hz, Ph-H),8.50 (d, 1H, J=5.2 Hz, pyrimidinyl-H),

(4-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine{14}

[0573]¹H-NMR (300 MHz, CDCl₃) δ2.45 (s, 3H, CH₃), 2.66 (s, 3H, CH₃),6.87 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (s, 1H, thienyl-H), 7.29 (m,2H, Ph-H), 7.60 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine{14}

[0574]¹H-NMR (300 MHz, CDCl₃) δ2.45 (s, 3H, CH₃), 2.68 (s, 3H, CH₃),6.91 (d, 1H, J =5.2 Hz, pyrimidinyl-H), 6.97 (m, 1H, Ph-H), 7.04 (s, 1H,thienyl-H), 7.28 (m, 1H, Ph-H), 7.38 (m, 2H, Ph-H), 8.44 (d, 1H, J=5.2Hz, pyrimidinyl-H), 8.60 (m, 1H, Ph-H).

(3-Chloro-phenyl)-(4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine{16}

[0575]¹H-NMR (300 MHz, CDCl₃) δ2.45 (s, 3H, CH₃), 2.70 (s, 3H, CH₃),6.90 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.20-7.33 (m, 3H, Ph-H andthienyl-H), 7.34 (m, 1H, Ph-H), 7.96 (m, 1H, Ph-H), 8.42 (d, 1H, J=5.2Hz, pyrimidinyl-H).

{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine{9}

[0576]¹H-NMR (300 MHz, d₆-DMSO) δ7.43 (d, 1H, J=5.2 Hz, pyrimidinyl-H),7.59 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H), 7.82 (m, 1H, Ph-H), 8.04 (m, 1H,Ph-H), 8.70 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 9.03 (s, 1H, thienyl-H).

Example 3 3-Dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone

[0577] A solution of 5-acetyl-2,4-dimethylthiazole (10 g, 60 mmol) inN,N-dimethylformamide dimethylacetal (10 mL) was refluxed under N₂.After 18 h, the reaction mixture was evaporated to dryness and theresidue was recrystallised from iPr₂O/CH₂Cl₂ to afford the titlecompound as a brown powder (9.94 g, 79%). ¹H-NMR (300 MHz, CDCl₃) δ2.66(s, 6H, CH₃), 2.70 (s, 6H, CH₃), 5.37 (d, 1H, J=12.2 Hz, CH), 7.66 (d,1H, J=12.2 Hz, CH).

Example 4 N-(3-Nitro-phenyl)-guanidine nitrate

[0578] A mixture of 3-nitroaniline (50 mmol, 6.90 g) in EtOH (10 mL) wascooled on an ice bath. Nitric acid (69% aq. soln.; 3.6 mL) was addeddropwise. To this mixture cyanamide (50% aq soln.; 5 mL) was added. Thereaction mixture was stirred at r.t. for 10 min and was then refluxedunder N₂ for a further 22 h. The solvent was evaporated. The dark brownsolid was washed with EtOAc/EtOH and dried under high vacuum overnightto afford the title compound as a brown solid (6.90 g, 57%). ¹H-NMR (300MHz, DMSO-d₆) δ7.66-7.75 (m, 2H, Ph-H), 8.09-8.14 (m, 2H, Ph-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine{12}

[0579] A mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21g) and N-(3-nitro-phenyl)-guanidine nitrate (1.0 mmol, 0.24 g) in2-methoxyethanol (5 mL) was treated with NaOH (40 mg). The reactionmixture was refluxed under N₂ for 20 h. The solvent was evaporated andthe residue was purified by flash chromatography (EtOAc/PE, 5:1) andrecrystallisation from EtOAc/MeOH to afford the title compound as ayellow solid (151 mg, 46%). M.p. 176-178° C. LC-MS: m/z=328 (M+1).C₁₅H₁₃N₅O₂S requires: C, 55.03; H, 4.00; N, 21.39; found: C, 54.67; H,3.88; N, 21.77. ¹H-NMR (300 MHz, CDCl₃) δ2.72 (s, 3H, CH₃), 2.74 (s, 3H,CH₃), 7.06 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.74-7.92 (m, 3H, Ph-H),8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.91 (t, 1H, J=4.3, 2.1 Hz,Ph-H).

Example 5 N-(4-Fluoro-phenyl)-guanidine nitrate

[0580] A solution of 4-fluoroaniline (25 mmol, 2.80 g) in EtOH (10 mL)was cooled on an ice bath. Nitric acid (69% aq. soln.; 1.8 mL) was addeddropwise. Then cyanamide (50% aq. soln.; 4 mL) was added. The reactionmixture was refluxed under N₂ for 21 h. The solvent was evaporated todryness. The solid residue was washed with EtOH and dried under highvacuum overnight to afford the title compound as a purple powder (2.54g, 47%). This material was used for subsequent reaction without furtherpurification.

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine{21}

[0581] To a mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21g) and N-(4-fluoro-phenyl)-guanidine nitrate (2.0 mmol, 0.44 g) in2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixture wasrefluxed under N₂ for 24 h. The solvent was evaporated to dryness andthe residue was purified by flash chromatography (EtOAc/PE, 2:1) andrecrystallisation from EtOAc/PE to afford the title compound as browncrystals (269 mg, 89%). ¹H-NMR (300 MHz, CDCl₃) δ2.69 (s, 3H, CH₃), 2.71(s, 3H, CH₃), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.03 (m, 2H, Ph-H),7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

Example 6 N-(2,4-Difluoro-phenyl)-guanidine nitrate

[0582] To a mixture of 2,4-difluoroaniline (25 mmol, 3.2 g) in EtOH (10mL) in an ice bath was added nitric acid (69% aq soln.; 1.8 mL)dropwise. After completion of the addition cyanamide (50% aq. soln.; 4mL) was added. The reaction mixture was refluxed under N₂ for 22 h. Thesolvent was evaporated. The solid residue was washed with EtOH and wasdried under high vacuum to afford the title compound as a purple solid(2.32 g, 40%).

(2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{22}

[0583] A mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21g) and N-(2,4-difluoro-phenyl)-guanidine nitrate (2 mmol, 0.47 g) in2-methoxyethanol (5 mL) was treated with NaOH (40 mg). After 24 hrefluxing under N₂ the solvent was evaporated to dryness and the residuewas purified by flash chromatography (EtOAc/PE, 2:1) andrecrystallisation from EtOAc/PE to afford the title compound as a brownpowder (250 mg, 79%). ¹H-NMR (300 MHz, CDCl₃) δ2.69 (s, 3H, CH₃), 2.71(s, 3H, CH₃), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (m, 2H, Ph-H),7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

Example 7 N-(4-Hydroxy-2-nitro-phenyl)-guanidine nitrate

[0584] A mixture of 4-amino-2-nitrophenol (25 mmol, 3.85 g) in EtOH (6mL) on an ice bath was treated with nitric acid (69% aq soln.; 1.8 mL).To this of cyanamide (50% aq. soln.; 4 mL) was added. The reactionmixture was refluxed under N₂ for 22 h. The solvent was evaporated. Thedark brown solid residue was washed with EtOH and was dried under highvacuum to afford the title compound as a grey solid (3.53 g, 54%).

4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino)-2-nitro-phenol{45}

[0585] 3-Dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1 mmol,0.21 g) in 2-methoxyethanol (5 mL) was treated withN-(4-hydroxy-2-nitro-phenyl)-guanidine nitrate (2 mmol, 0.52 g) in thepresence of NaOH (40 mg). The reaction mixture was refluxed under N₂ for24 h. The solvent was evaporated to dryness and the residue was purifiedby flash chromatography (EtOAc) and recrystallisation from EtOAc/PE toafford the title compound as a yellow powder (61 mg). ¹H-NMR (300 MHz,CDCl₃) δ2.71 (s, 3H, CH₃), 2.73 (s, 3H, CH₃), 7.01 (d, 1H, J=5.2 Hz,pyrimidinyl-H), 7.18 (m, 1H, Ph-H), 7.64 (m, 1H, Ph-H), 8.42 (d, 1H, J5.2 Hz, pyrimidinyl-H), 8.75 (d, 1H, J=2.7 Hz, Ph-H), 10.45 (br. s, 1H,OH).

[0586] The following compounds were prepared in a manner analogous tothat described above:

(2-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{5}

[0587]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.96-7.02 (m, 2H, pyrimidinyl-H and Ph-H), 7.30-7.42 (m, 2H, Ph-H), 8.46(d, 1H, J=5.3 Hz, pyrimidinyl-H). 8.54-8.58 (m, 1H, Ph-H).

(3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{7}

[0588]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 6H, CH₃), 6.97-7.04 (m, 2H,pyrimidinyl-H and Ph-H), 7.23-7.36 (m, 2H, Ph-H), 7.94 (t, 1H, J=1.9,3.9 Hz, Ph-H), 8.43 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{6}

[0589]¹H-NMR (300 MHz, CDCl₃) δ2.70 (s, 3H, CH₃), 2.71 (s, 3H, CH₃),6.96 (d, 2H, J=5.3 Hz, pyrimidinyl-H), 7.33 (m, 2H, Ph-H), 7.60 (m, 2H,Ph-H), 8.42 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine{20}

[0590]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.98-7.22 (m, 4H, pyrimidinyl-H and Ph-H), 8.45 (d, 1H, J=5.3 Hz,pyrimidinyl-H). 8.50 (m, 1H, Ph-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine{35}

[0591]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.75 (m, 1H, Ph-H), 7.00 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.17-7.32 (m,3H, Ph-H), 7.77 (m, 1H, Ph-H), 8.44 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl)-amine{23}

[0592]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.73 (s, 3H, CH₃),6.49 (m, 1H, Ph-H), 7.02 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.28-7.34 (m,2H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-amine{24}

[0593]¹H-NMR (300 MHz, CDCl₃) δ2.72 (s, 6H, CH₃), 7.01-7.04 (m, 2H,pyrimidinyl-H and Ph-H), 7.67 (m, 2H, Ph-H), 8.45 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

(2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine {25}

[0594]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),7.02 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.29-7.42 (m, 2H, Ph-H), 8.46 (d,1H, J=5.3 Hz, pyrimidinyl-H), 8.54 (d, 1H, J=8.9 Hz, Ph-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl)-(2-trifluoromethyl-phenyl)-amine{27}

[0595]¹H-NMR (300 MHz, CDCl₃), 2.69 (s, 3H, CH₃), 2.70 (s, 3H, CH₃),7.00 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.19 (m, 1H, Ph-H), 7.59-7.65 (m,2H, Ph-H), 8.37 (d, 1H, J =6.4 Hz, Ph-H), 8.44 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl)-(3-trifluoromethyl-phenyl)-amine{26}

[0596]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),7.01 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.29-7.34 (m, 2H, Ph-H), 7.45 (m,1H, Ph-H), 7.64 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

{4-2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine{28}

[0597] Orange solid. M.p. 183-185° C. LC-MS: m/z=351.4 (M+1).C₁₆H₁₃F₃N₄S requires: C, 54.85; H, 3.74; N, 15.99; found: C, 54.71; H,3.59; N, 16.26. ¹H-NMR (300 MHz, CDCl₃) δ2.72 (s, 3H, CH₃), 2.73 (s, 3H,CH₃), 7.03 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.60 (m, 2H, Ph-H), 7.79(m, 2H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(2-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{29}

[0598]¹H-NMR (300 MHz, CDCl₃), 2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.92 (m, 1H, Ph-H), 7.00 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.38 (m, 1H,Ph-H), 7.59 (m, 2H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.51(m, 1H, Ph-H).

(3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{30}

[0599]¹H-NMR (300 MHz, CDCl₃) δ2.72 (s, 6H, CH₃), 6.98 (d, 1H, J=5.3 Hz,pyrimidinyl-H), 7.19 (m, 2H, Ph-H), 7.41 (m, 1H, Ph-H), 8.11 (m, 1H,Ph-H), 8.44 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{31}

[0600] Yellow solid. M.p. 173-175° C. LC-MS: m/z=363 (M+1). C₁₅H₁₃BrN₄Srequires: C, 49.87; H, 3.63; N, 15.51; found: C, 49.81; H, 3.61; N,15.56. ¹H-NMR (300 MHz, CDCl₃) δ2.70 (s, 3H, CH3), 2.72 (s, 3H, CH3),6.97 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.47 (m, 2H, Ph-H), 7.55 (m, 2H,Ph-H), 8.42 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine{32}

[0601]¹H-NMR (300 MHz, CDCl₃) δ2.70 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.80 (m, 1H, Ph-H), 6.99 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.42 (m, 1H,Ph-H), 7.84 (m, 1H, Ph-H), 8.39 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine{33}

[0602]¹H-NMR (300 MHz, d₆-DMSO) δ: 2.68 (s, 6H, CH₃), 7.03 (m, 2H,pyrimidinyl-H and Ph-H), 7.28 (d, 1H, J=7.9 Hz, Ph-H), 7.68 (m, 1H,Ph-H), 8.41 (m, 1H, Ph-H), 8.47 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine{34}

[0603] Yellow solid. M.p. 171-173° C. LC-MS:=m/z 409 (M+1). C₁₅H₁₃IN₄Srequires: C, 44.13; H, 3.21; N, 13.72; found: C, 44.03; H, 3.17; N,13.73. ¹H-NMR (300 MHz, d₆-DMSO) δ2.70 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.97 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.46 (m, 1H, Ph-H), 7.64 (m, 2H,Ph-H), 8.42 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

(3,4-Difluoro-phenyl)-(4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{36}

[0604]¹H-NMR (300 MHz, d₆-DMSO) δ2.70 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.98 (d, 1H, J =5.3 Hz, pyrimidinyl-H), 7.11 (m, 2H, Ph-H), 7.83 (m, 1H,Ph-H), 8.43 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl/-(3-methoxy-phenyl)-amine{38}

[0605]¹H-NMR (300 MHz, CDCl₃) δ2.70 (s, 3H, CH₃), 2.71 (s, 3H, CH₃),3.86 (s, 3H, OCH₃), 6.61 (m, 1H, Ph-H), 6.94 (d, 1H, J=5.3 Hz,pyrimidinyl-H), 7.10-7.28 (m, 3H, Ph-H), 8.42 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine{37}

[0606]¹H-NMR (300 MHz, CDCl₃) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),3.92 (s, 3H, OCH₃), 6.89-7.04 (d, 4H, Ph-H and pyrimidinyl-H), 8.43 (d,1H, J=5.3 Hz, pyrimidinyl-H), 8.53 (m, 1H, Ph-H).

{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine{39}

[0607] Orange-yellow solid. M.p. 137-139° C. LC-MS: m/z=313 (M+1).C₁₆H₁₆N₄OS requires: C, 61.51; H, 5.16; N, 17.94; found: C, 61.32; H,5.18; N, 18.36. ¹H-NMR (300 MHz, CDCl₃), 2.68 (s, 3H, CH₃), 2.70 (s, 3H,CH₃), 3.82 (s, 3H, OCH₃), 6.88-6.93 (d, 4H, Ph-H and pyrimidinyl-H),7.52 (m, 1H, Ph-H), 8.37 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol {40}

[0608]¹H-NMR (300 MHz, d₆-DMSO) δ2.67 (s, 3H, CH₃), 2.68 (s, 3H, CH₃),6.42 (d, 1H, J =8.0 Hz, Ph-H), 6.94 (d, 1H, J=5.2 Hz, pyrimidinyl-H),7.05 (m, 1H, Ph-H), 7.24 (m, 2H, Ph-H), 7.99 (m, 1H, Ph-H), 8.43 (d, 1H,J=5.2 Hz, pyrimidinyl-H), 8.99 (br. s, 1H, NH), 9.21 (br. s, 1H, OH).

4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol {41}

[0609]¹H-NMR (300 MHz, d₆-DMSO) δ2.61 (s, 3H, CH₃), 2.64 (s, 3H, CH₃),6.71 (m, 2H, Ph-H), 6.97 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.49 (m, 2H,Ph-H), 7.24 (m, 2H, Ph-H), 8.43 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 9.06(br. s, 1H, NH), 9.32 (br. s, 1H, OH).

4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile {48}

[0610]¹H-NMR (300 MHz, d₆-DMSO), 2.65 (s, 3H, CH₃), 2.67 (s, 3H, CH₃),7.22 (d, 1H, J =5.2 Hz, pyrimidinyl-H), 7.77 (m, 2H, Ph-H), 7.99 (m, 2H,Ph-H), 8.61 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 10.2 (s, 1H, NH).

3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile {49}

[0611]¹H-NMR (300 MHz, d₆-DMSO) δ2.71 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),7.03 (d, 1H, J =5.2 Hz, pyrimidinyl-H), 7.31-7.45 (m, 2H, Ph-H), 7.67(m, 1H, Ph-H), 8.29 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.2 Hz,pyrimidinyl-H).

4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acid {53}

[0612]¹H-NMR (300 MHz, CDCl₃) δ2.65 (s, 3H, CH₃), 2.67 (s, 3H, CH₃),7.09 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.70 (m, 2H, Ph-H), 7.82 (m, 2H,Ph-H), 8.52 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acidmethyl ester {50}

[0613]¹H-NMR (300 MHz, CDCl₃) δ2.72 (s, 3H, CH₃), 2.73 (s, 3H, CH₃),3.91 (s, 3H, OCH₃), 7.02 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.41 (sbr,1H, NH), 7.76 (m, 2H, Ph-H), 8.05 (m, 2H, Ph-H), 8.47 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

(3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{51}

[0614]¹H-NMR (300 MHz, CDCl₃) δ2.45 (s, 3H, CH₃), 2.71 (s, 6H, CH₃),6.99 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.18-7.32 (m, 2H, Ph-H), 7.82 (m,1H, Ph-H), 8.41 (d, 1H, J =5.3 Hz, pyrimidinyl-H).

(3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{52}

[0615]¹H-NMR (300 MHz, CDCl₃) δ2.70 (s, 3H, CH₃), 2.71 (s, 3H, CH₃),3.90 (s, 3H, OCH₃), 6.92 (m, 2H, pyrimidinyl-H & Ph-H), 7.10 (sbr, 1H,NH), 7.38 (m, 1H, Ph-H), 7.85 (m, 1H, Ph-H), 8.40 (d, 1H, J=5.3 Hz,pyrimidinyl-H).

5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester {98}

[0616]¹H-NMR (300 MHz, d₆-DMSO) (2.64 (s, 3H, CH₃), 2.66 (s, 3H, CH₃),3.29 (s, 3H, OCH₃), 3.66 (m, 2H, CH₂), 4.44 (m, 2H, CH₂), 7.13 (d, 1H,J=5.3 Hz, pyrimidinyl-H), 7.32 (m, 1H, Ph-H), 7.98 (m, 1H, Ph-H), 8.39(m, 1H, Ph-H), 8.54 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 9.93 (s, 1 H, NH).

Example 8 4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamine

[0617] This compound was prepared by heating equimolar amounts of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and guanidine inrefluxing 2-methoxethanol. ¹H-NMR (300 MHz, CDCl₃), 2.67 (s, 3H, CH₃),2.68 (s, 3H, CH₃), 5.14 (br, 2H, NH₂), 6.83 (d, 1H, J=5.3 Hz,pyrimidinyl-H), 8.30 (d, 1H, J=5.3 Hz, pyrimidinyl-H).

N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide{42}

[0618] A solution of 4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamine(1 mmol, 0.227 g), 3-nitrobenenesulfonyl chloride (1.5 mmol, 0.33 g) inpyridine (4 mL) was stirred at r.t. for 24 h. The reaction mixture wasevaporated to dryness. The dark brown residue was dissolved in EtOAc andwas washed with 2M aq HCl solution, water, brine and was dried overMgSO₄. Concentration gave a light yellow residue and this was purifiedby flash chromatography (EtOAc/PE, 5:1) and recrystallisation fromEtOAc/MeOH to afford the title compound as yellow crystals (44 mg).¹H-NMR (300 MHz, CDCl₃) δ2.68 (s, 3H, CH₃), 2.73 (s, 3H, CH₃), 7.59 (d,1H, J=5.3 Hz, pyrimidinyl-H), 7.90 (m, 1H, Ph-H), 8.60 (m, 1H, Ph-H),8.75 (m, 1H, Ph-H), 8.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.15 (t, 1H,J=1.98, 3.91 Hz, Ph-H).

Example 93-Dimethylamino-1-(4-methyl-2-methylamino-thiazol-5-yl)-propenone

[0619] A solution of 3-chloro-2,4-pentadione (2.5 g, 19 mmol) in MeOH(15 mL) treated with N-methyl-2-thiourea (1.67 g, 19 mmol) and pyridine(1.5 mL). The reaction mixture was stirred at r.t. for 2-3 h. Theresulting precipitates were filtered and washed with Et₂O to afford awhite solid product of 5-acetyl-2-methylamino-4-methylthiazol, which wasused in the next reaction step without further purification. A mixtureof this product (2.05 g) in N,N-dimethylformamide dimethyl acetal (10mL) was heated at 100-110° C. for 22 h. The reaction mixture wasconcentrated. The precipitate was collected and washed with EtOAc toafford the title compound as an orange solid. ¹H-NMR (300 MHz, CDCl₃)δ2.55, 2.94 (s, 6H, CH₃), 3.40 (s, 6H, NCH₃), 5.29 (d, 1H, J=12.2 Hz,CH), 7.62 (d, 1H, J=12.2 Hz, CH).

Example 10(4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{62}

[0620] A mixture3-dimethylamino-1-(4-methyl-2-methylamino-thiazol-5-yl)-propenone (1mmol, 0.22 g) and N-(4-fluoro-phenyl)-guanidine nitrate (2 mmol, 0.44 g)in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixturewas heated at 110-120° C. under N₂ for 20 h. The solvent was evaporatedto dryness and the residue was purified by flash chromatography, usingEtOAc/PE (1:1, v/v) to elute the product as a yellow solid.Recrystallisation from EtOAc/MeOH yielded 230 mg brown crystals of puretitle compound. ¹H-NMR (300 MHz, d₆-DMSO) δ2.46 (s, 3H, CH₃), 2.86 (d,3H, CH₃), 6.90 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.11 (m, 2H, Ph-H),7.76 (m, 2H, Ph-H), 8.07 (m, 1H, NH), 8.32 (d, 1H, J=5.4 Hz,pyrimidinyl-H), 9.48 (s, 1H, NH).

[0621] The following compounds were prepared in a manner analogous tothat described above:

4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol{62}

[0622]¹H-NMR (300 MHz, CD₃OD₃) δ2.53 (s, 3H, CH₃), 2.98 (s, 3H, CH₃),6.77 (d, 2H, J=8.8 Hz, Ph-H), 6.86 (d, 1H, J=5.5 Hz, pyrimidinyl-H),7.44 (d, 2H, J=8.8 Hz, Ph-H), 8.21 (d, 1 H, J=5.5 Hz, pyrimidinyl-H).

(4-Iodo-phenyl)-{4-4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine {72}

[0623] Yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.50 (s, 3H, CH₃), 2.92(d, 6H, CH₃), 6.85 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.53 (d, 2H, J=8.8Hz, Ar-H), 7.65 (d, 2H, J =8.8 Hz, Ar-H), 8.28 (d, 1H, J=5.4 Hz,pyrimidinyl-H) 9.41 (s, 1H, NH).

{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine{76}

[0624] Yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.80 s, 3H, CH₃), 3.09(s, 3H, CH₃), 7.01 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.55 (m, 1H, Ph-H),7.79 (d, 1H, Ph-H), 8.02 (d, 1H, Ph-H), 8.15 (m, 1H, NH), 8.41 (d, 1H,J=5.4 Hz, pyrimidinyl-H), 9.00 (s, 1H, Ph-H), 10.02 (s, 1H, NH). DEMALDI-TOF MS: {M+H}⁺=345.15 (C₁₅H₁₄N₆O₂S requires 342.38).

3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol{85}

[0625] Yellow crystals. ¹H-NMR (300 MHz, d₆-DMSO) δ2.86 (s, 3H, CH₃),3.24 (s, 3H, CH₃), 6.36 (m, 1H, Ph-H), 6.88 (d, 1H, J=5.5 Hz,pyrimidinyl-H), 7.03 (m, 1H, Ph-H), 7.24 (m, 1H, Ph-H), 8.06 (m, 1H,NH), 8.32 (d, 1H, J=4.5 Hz, pyrimidinyl-H), 9.21 (s, 1H, Ph-H), 9.31 (s,1H, NH). DE MALDI-TOF MS: {M+H}⁺ =315.92 (C ₁₅H₁₅N₆OS requires 313.38).

(4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{86}

[0626] Yellow-brown solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.86 (s, 3H, CH₃),3.09 (s, 3H, CH₃), 6.93 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.43 (m, 2H,Ph-H), 7.75 (m, 2H, Ph-H), 8.07 (m, 1H, NH), 8.34 (d, 1H, J=5.5 Hz,pyrimidinyl-H), 9.61 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=378.8(C₁₅H₁₄N₆SBr requires 376.28).

(4-Chloro-phenyl)-≡4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{87}

[0627] Tan crystals. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 (s, 3H, CH₃), 3.23(s, 3H, CH₃), 6.94 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.32 (m, 2H, Ph-H),7.81 (m, 2H, Ph-H), 8.09 (m, 1H, NH), 8.35 (d, 1H, J=5.7 Hz,pyrimidinyl-H), 9.61 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=332.1(C₁₅H₁₄N₆SCl requires 331.8).

(3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{88}

[0628] Light-yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.85 (s, 3H, CH₃),3.09 (s, 3H, CH₃), 3.78 (s, 3H, CH₃), 6.52 (m, 1H, Ph-H), 6.92 (d, 1H,J=5.5 Hz, pyrimidinyl-H), 7.16 (m, 1H, Ph-H), 7.29 (m, 1H, Ph-H), 7.56(s, 1H, Ph-I), 8.10 (m, 1H, NH), 8.35 (d, 1H, J=5.3 Hz, pyrimidinyl-H),9.45 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=327.8 (C₁₆H₁₇N₅OS requires327.4).

{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine{89}

[0629] Yellow-brown solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.88 (s, 3H, CH₃),3.10 (s, 3H, CH₃), 7.01 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.62 (m, 2H,Ph-H), 8.01 (m, 2H, Ph-H), 8.12 (m, 1H, NH), 8.40 (d, 1H, J=5.5 Hz,pyrimidinyl-H), 9.91 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=365.5(C₁₆H₁₄N₅SF₃ requires 365.4).

{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine{90}

[0630] Yellow-brown solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.86 (s, 3H, CH₃),3.11 (s, 3H, CH₃), 6.99 (d, 1H, J=5.5 Hz, Ph-H), 7.27 (m, 1H, Ph-H),7.50 (m, 1H, Ph-H), 7.87 (m, 1H, Ph-H), 8.15 (m, 1H, NH), 8.40 (d, 1H,J=5.4 Hz, pyrimidinyl-H), 8.47 (s, 1H, Ph-H), 9.86 (s, 1H, NH). DEMALDI-TOF MS: {M+H}⁺=369.8 (C₁₆H₁₄N₅SF₃ requires 365.4).

(3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{83}

[0631] Yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 (s, 3H, CH₃), 3.11(s, 3H, CH₃), 6.96 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.10 (m, 1H, Ph-H),7.23 (m, 1H, Ph-H), 7.62 (m, 1H, Ph-H), 8.15 (m, 1H, NH), 8.31 (s, 1H,Ph-H), 8.38 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.70 (s, 1H, NH). DEMALDI-TOF MS: {M+H}⁺ =377.4 (C ₁₅H₁₄N₆SBr requires 376.3).

(3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{108}

[0632] Yellow crystals. ¹H-NMR (300 MHz, d₆-DMSO) δ2.86 (s, 3H, CH₃),3.10 (s, 3H, CH₃), 6.95 (d, 2H, J=5.7 Hz, pyrimidinyl-H), 7.29 (m, 1H,Ph-H), 7.61 (m, 1H, Ph-H), 8.14 (s, 1H, Ph-H), 8.38 (d, 1H, J=4.3 Hz,pyrimidinyl-H), 9.72 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=331.6(C₁₅H₁₄N₆SCl requires 331.8).

(3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl;56-amine {102}

[0633] Yellow crystals. ¹H-NMR (30 MHz, d₆-DMSO) δ2.88 (s, 3H, CH₃),3.10 (s, 3H, CH₃), 6.96 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.07 (m, 1H,Ph-H), 7.28 (m, 1H, Ph-H), 7.61 (m, 1H, Ph-H), 8.14 (m, 1H, NH), 8.37(d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.50 (s, 1H, Ph-H), 9.64 (s, 1H, NH).DE MALDI-TOF MS: {M+H}⁺=423.3 (C₁₅H₁₄N₆SI requires 423.3).

(3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{103}

[0634] Yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 (s, 3H, CH₃), 3.10(s, 3H, CH₃), 6.74 (m, 1H, Ph-H), 6.97 (d, 1H, J=5.4 Hz, pyrimidinyl-H),7.29 (m, 1H, Ph-H), 7.47 (m, 1H, Ph-H), 7.87 (m, 1H, Ph-H), 8.12 (m, 1H,NH), 8.38 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 9.71 (s, 1H, NH). DEMALDI-TOF MS: {M+H}⁺=316.3 (C₁₅H₁₄N₅SF requires 315.4).

(3,3-Difluoro-phenyl)-{4-4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{106}

[0635] Yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 (s, 3H, CH₃), 3.10(s, 3H, CH₃), 6.74 (m, 1H, Ph-H), 7.02 (d, 1H, J=5.5, pyrimidinyl-H),7.60 (m, 2H, Ph-H), 8.18 (m, 1H, NH), 8.41 (d, 1H, J=5.4 Hz,pyrimidinyl-H), 9.92 (s, 1H, NH). DE MALDI-TOF MS: {M+H}⁺=333.4(C₁₅H₁₃N₅SF₂ requires 333.4).

(4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{107}

[0636] Light-yellow crystals. ¹H-NMR (300 MHz, d₆-DMSO) δ2.86 (s, 3H,CH₃), 3.10 (s, 3H, CH₃), 7.01 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.61 (m,1H, Ph-H), 7.92 (m, 1H, Ph-H), 8.17 (m, 1H, NH), 8.40 (d, 1H, J=5.5 Hz,Ph-H), 8.53 (s, 1H, Ph-H), 9.96 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=399.8 (C₁₆H₁₃N₃SClF₃ requires 399.8).

(3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{104}

[0637] Light-yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 s, 3H, CH₃),3.12 (s, 3H, CH₃), 6.97 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.35 (m, 1H,Ph-H), 8.04 (d, 1H, Ph-H), 8.08 (d, 1H, Ph-H), 8.20 (m, 1H, NH), 8.37(d, 1H, J=5.3, pyrimidinyl-H), 9.71 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=333.8 (C₁₅H₁₃N₅SF₂ requires 333.4).

(2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine{105}

[0638] Light-yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ: 2.84 (s, 3H,CH₃), 3.10 (s, 3H, CH₃), 6.86 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.06 (m,1H, Ph-H), 7.29 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H), 8.04 (m, 1H, NH),8.26 (d, 1H, J=5.3, pyrimidinyl-H), 8.92 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=334.2 (C₁₅H₁₃N₅SF₂ requires 333.4).

(4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine {109}

[0639] Green-yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.87 (s, 3H, CH₃),3.35 (s, 3H, CH₃), 3.74 (s, 3H, CH₃), 6.85 (m, 1H, pyrimidinyl-H), 6.86(m, 2H, Ph-H), 7.66 (m, 2H, Ph-H), 8.02 (m, 1H, NHCH₃), 8.29 (d, 1H,J=5.4 Hz, pyrimidinyl-H), 9.25 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=327.8 (C₁₆H₁₇N₅OS requires 327.4).

2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester {101}

[0640] Yellow crystals. ¹H-NMR (30 MHz, d₆-DMSO) δ2.88 (s, 3H, CH₃),3.10 (s, 3H, CH₃), 3.82 (s, 3H, CH₃), 7.05 (d, 1H, J=5.5,pyrimidinyl-H), 7.73 (d, 1H, J=8.8 Hz, Ph-H), 7.85 (d, 1H, J=8.7 Hz,Ph-H), 8.20 (m, 1H, NHCH₃), 8.27 (s, 1H, Ph-H), 8.43 (d, 1H, J=5.6 Hz,pyrimidinyl-H). DE MALDI-TOF MS: {M+H}⁺=388.8 (C₁₇H₁₆N₅O₂SCl requires389.9).

Example 113-Dimethylamino-1-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-propenone

[0641] A mixture of 5-chloro-pentadione (5.12 g, 38 mmol) andthionicotinamide (5.25 g, 38 mmol) in MeOH (10 mL) was treated withpyridine (3 mL). The reaction mixture was heated at 70-75° C. for 5 h.The solvent was evaporated. The resulting solid was filtered and washedwith EtOAc/MeOH to afford 4.33 g 5-acetyl-4-methyl-2-(3-pyridyl)-thiazolas a yellow solid, which was subjected to the next reaction withoutfurther purification. A mixture of this material (2.0 g) andN,N-dimethylformamide dimethyl acetal (4 mL) was heated at 80° C. for 22h. The reaction mixture was concentrated and then triturated withEtOAc/PE. The precipitates were collected and washed with EtOAc/PE toafford the title compound (2.05 g, 75%) as a grey solid. ¹H-NMR (300MHz, CDCl₃) δ2.80 (s, 6H, CH₃), 3.50 (s, 3H, CH₃), 5.47 (d, 1H, J=12.1Hz, CH), 7.39 (m, 1H, Ar-H), 7.78 (d, 1H, J=12.1 Hz, CH), 8.28 (m, 1H,Ar-H), 8.66 (m, 1H, Ar-H), 9.16 (s, 1H, Ar-H).

Example 12 {4-4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-phenyl)-amine {71}

[0642] To a mixture of3-dimethylamino-1-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-propenone (1mmol, 0.27 g) and N-(3-nitro-phenyl)-guanidine nitrate (1 mmol, 0.24 g)in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixturewas heated at 120° C. under N₂ for 20 h. The solvent was evaporated todryness and the residue was purified by flash chromatography, usingEtOAc/PE (2:1, v/v) to elute the product, which was recrystallized fromMeOH to afford the title compound (154 mg) as light-yellow crystals.¹H-NMR (300 MHz, d₆-DMSO) δ2.82 (s, 3H, CH₃), 7.24 (d, 1H, J=5.2 Hz,pyrimidinyl-H), 7.53 (m, 2H, Ar-H), 7.82 (m, 1H, Ph-H), 8.00 (m, 1H,Ar-H), 8.09 (s, 1H, Ar-H), 8.35 (m, 1H, Ar-H), 8.61 (d, 1H, J=5.2 Hz,Py-H), 8.68 (m, 1H, Ar-H), 10.23 (s, 1 H, NH).

[0643] The following compound was prepared in a manner analogous to thatdescribed above:

(4-Fluoro-phenyl)-{4-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-amine{67}

[0644]¹H-NMR (300 MHz, d₆-DMSO) δ2.78 (s, 3H, CH₃), 7.22 (m, 2H,pyrimidinyl-H, Ar-H), 7.59 (m, 1H, Ar-H), 7.82 (m, 2H, Ar-H), 8.38 (m,1H, Ar-H), 8.60 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.72 (m, 1H, Ar-H),9.21 (s, 1H, Ar-H), 9.83 (s, 1H, NH).

Example 13

[0645]1-(2,4-Dimethyl-thiazol-5-yl)-3-(4-trifluoromethyl-phenyl)-propenone Toan ice-cold solution of NaOH (2.2 g) in H₂O (10 mL)2,4-dimethyl-5-acetylthiazol (43 mmol, 6.6 g) was added. After 5 minstirring this was treated with trifluoro-p-tolualdehyde (43 mmol, 7.49g). The reaction mixture was warmed to r.t. and stirred for 2 h. It wasdiluted with CH₂Cl₂, washed with HCl/H₂O, brine and was dried overMgSO₄. The solvent was evaporated to afford the title compound (4.86 g).

Example 144-{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino}-2-nitro-phenol{66}

[0646] A mixture of1-(2,4-dimethyl-thiazol-5-yl)-3-(4-trifluoromethyl-phenyl)-propenone (1mmol, 0.31 g) and N-(4-hydroxy-3-nitro-phenyl)-guanidine nitrate (1.5mmol, 0.39 g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). Thereaction mixture was heated at 120° C. under N₂ for 20 h. The solventwas evaporated to dryness and the residue was purified by flashchromatography, using EtOAc/PE (2:1, v/v) to elute the product, whichwas recrystallized from MeOH/EtOAc to afford the title compound (178 mg)as orange crystals. ¹H-NMR (300 MHz, CDCl₃) δ2.75 (s, 3H, CH₃), 2.79 (s,3H, CH₃), 7.18 (m, 1H, Ar-H), 7.44 (s, 1H, pyrimidinyl-H), 7.61 (m, 1H,Ar-H), 7.81 (m, 2H, Ar-H), 8.22 (m, 2H, Ar-H), 8.98 (m, 1H, Ar-H).

[0647] The following compounds were prepared in a manner analogous tothat described above:

{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine{64}

[0648]¹H-NMR (300 MHz, CDCl₃) δ2.73 (s, 3H, CH₃), 2.78 (s, 3H, CH₃),7.05 (m, 2H, Ar-H), 7.36 (s, 1H, pyrimidinyl-H), 7.78 (m, 4H, Ar-H),8.22 (m, 2H, Ar-H), 8.67 (sbr, 1H, NH).

(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine{65}

[0649]¹H-NMR (300 MHz, CDCl₃) δ2.73 (s, 3H, CH₃), 2.79 (s, 3H, CH₃),7.29 (m, 2H, Ar-H), 7.39 (s, 1H, pyrimidinyl-H), 7.80 (m, 4H, Ar-H),8.22 (m, 2H, Ar-H), 8.96 (sbr, 1H, NH).

{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine{57}

[0650]¹H-NMR (300 MHz, d₆-DMSO) δ2.68(s, 3H, CH₃), 2.75 (s, 3H, CH₃),7.61 (m, 4H, Ar-H), 7.84 (m, 1H, Ar-H), 8.08 (m, 1H, Ar-H), 8.27 (m, 2H,Ar-H), 9.15 (s, 1H, Ar-H), 10.3 (s, 1H, NH).

4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol{70}

[0651]¹H-NMR (300 MHz, d₆-DMSO) δ2.67 (s, 3H, CH₃), 2.72 (s, 3H, CH₃),6.93 (m, 2H, Ar-H), 7.18 (m, 2H, Ar-H), 7.42 (s, 1H, pyrimidinyl-H),7.84 (m, 2H, Ar-H), 8.09 (m, 2H, Ar-H), 9.67 (s, 1H, NH or OH), 10.11(s, 1H, NH or OH).

Example 15{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine{91}

[0652] To a mixture of1-(2-allylamino-4-methyl-thiazol-5-yl)-3-dimethylamino-propenone (1.0mmol, 0.25 g) and N-(3-nitro-phenyl)-guanidine nitrate (1.5 mmol, 0.36g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reactionmixture was heated at 110-120° C. under N₂ for 22 h. The solvent wasevaporated to dryness and the residue was purified by flashchromatography, using EtOAc/PE (1:1, v/v) to elute the product as yellowsolid. Recrystallisation from EtOAc/MeOH yielded the title compound asbrown crystals. ¹H-NMR (300 MHz, d₆-DMSO) δ2.51 (s, 3H, CH₃), 3.92 (sbr,2H, CH₂), 5.20 (m, 2H, CH₂), 5.91 (m, 1H, CH), 7.02 (d, 1H, J=5.5 Hz,pyrimidinyl-H ), 7.57 (m, 2H, Ph-H), 7.80 (m, 1 H, Ph-H), 8.06 (m, 1H,Ph-H), 8.43 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 8.94 (s, 1H, Ph-H), 10.04(s, 1H, NH).

[0653] The following compound was prepared in a manner analogous to thatdescribed above:

{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine{82}

[0654]¹H-NMR (300 MHz, d₆-DMSO) δ2.51 (s, 3H, CH₃), 3.92 (sbr, 2H, CH₂),5.24 (m, 2H, CH₂), 5.91 (m, 1H, CH), 6.90 (d, 1H, J=5.5 Hz,pyrimidinyl-H), 7.11 (m, 2H, Ph-H), 7.76 (m, 2H, Ph-H), 8.33 (d, 1H,J=5.5 Hz, pyrimidinyl-H), 9.49 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=341.4 (C₁₇H₁₆FN₅S requires 341.4).

Example 16{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine{75}

[0655] A mixture of3-dimethylamino-1-(2-ethylamino-4-methyl-thiazol-5-yl}-propenone (1mmol, 0.24 g) and NaOH (40 mg) in 2-methoxylethanol (5 mL) was treatedwith of N-4-fluoro-phenyl)-guanidine nitrate (0.36 g, 1.5 mmol). Thereaction mixture was heated at 110-120° C. under N₂ for 20 h. Afterconcentration, the residue was filtered and washed with MeOH.Recrystallisation from EtOAc/MeOH afforded the title compounds (291 mg)as a yellow solid. ¹H-NMR (300 MHz, d₆-DMSO) δ1.17 (m, 3H, CH₃), 2.51(s, 3H, CH₃), 3.26 (m, 2H, CH₃), 6.89 (d, 1H, J=5.5 Hz, pyrimidinyl-H),7.11 (m, 2H, Ph-H), 7.77 (m, 2H, Ph-H), 8.33 (d, 1H, J=5.5 Hz,pyrimidinyl-H). DE MALDI-TOF MS: {M+H}⁺=331.2 (C₁₆H₁₆FN₅S requires329.4).

Example 17

[0656]4-{4-{2-(4-Nitro-phenylamino)-thiazol-5-yl)-pyrimidin-2-ylamino)-phenol{111}

[0657] A mixture of3-dimethylamino-1-2-(4-nitro-phenylamino)-thiazol-5-yl}-propenone (1mmol, 0.32 g) and NaOH (50 mg) in 2-methoxylethanol (5 mL) was treatedwith N-(4-hydroxy-phenyl)-guanidine nitrate (0.32 g, 1.5 mmol). Thereaction mixture was heated at 110-120° C. under N₂ for 6 h. Afterconcentration, the residue was filtered and washed with MeOH.Recrystallisation from MeOH afforded the title compound as an orangesolid. ¹H-NMR (300 MHz, d₆-DMSO) δ6.67 (m, 2H, Ph-H), 6.93 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.48 (m, 2H, Ph-H), 7.86 (m, 2H, Ph-H), 8.26(m, 2H, Ph-H), 8.36 (d, 1H, J=5.3 Hz, pyrimidinyl-H). DE MALDI-TOF MS:{M+H}⁺=406.82 (C₁₉H₁₄N₆O₃S requires 406.42).

Example 18N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine{115}

[0658] To a mixture of{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine(3.97 mmol, 1.3 g) in 2-methoxyethanol (15 mL) was added AcOH (1 mL).The reaction mixture was stirred under N₂ for 10 min. Palladium catalyst(660 mg; 10% on activated carbon) was the added and the reaction mixturewas allowed to stir under H₂ for 18 h. The reaction mixture was passedthrough Celite 521 and the precipitates were washed several times withMeOH. The filtrate was concentrated and recrystallised from MeOH/EtOActo afford grey crystals ofN-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine. Analiquot of this material (500 mg) in 2-methoxylethanol was cooled on anice bath and was treated with HCl (conc. 1 mL). Cyanamide (50% aq soln.,4 mL) was added dropwise. After completion of the addition the reactionmixture was warmed to r.t. and heated at reflux for 20 h. The reactionmixture was concentrated. The residue was diluted with EtOAc and washedwith water and brine. The organic phase was evaporated and purified bychromatography, using EtOAc/MeOH (3:1, v/v) to elute the title compound.DE MALDI-TOF MS: {M+H}⁺=339.16 (C₁₆H₁₇N₇S requires 339.42).

Example 19{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-methanol{116}

[0659] A mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (10 mmol, 2.1 g)in 2-methoxylethanol was treated withN-(4-hydroxymethyl-phenyl)-guanidine hydrochloride (1.65 g) in thepresence of NaOH (400 mg). The reaction mixture was allowed to refluxfor 20 h. After concentration, the precipitates were filtered and washedwith EtOAc/MeOH several times. Recrystallisation from MeOH/EtOAcafforded the title compound (2.17 g, 70%). ¹H-NMR (300 MHz, d₆-DMSO)δ3.00 (s, 3H, CH₃), 3.02 (s, 3H, CH₃), 4.86 (s, 2H, CH₂), 7.30 (m, 1H,Ph-H), 7.44 (d, 1H, J=6.1 Hz, pyrimidinyl-H), 7.61 (m, 1H, Ph-H), 8.01(m, 1H, Ph-H), 8.13 (s, 1H, Ph-H), 8.88 (d, 1H, J=6.1 Hz,pyrimidinyl-H).

Example 20{3-(2-Diethylamino-ethoxymethyl)-phenyl}-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine{118}

[0660] A solution of{3-{4-(2,4-dimethyl-thaizol-5-yl)-pyrimidin-2-ylamino}-phenyl}-methanol(1 mmol, 0.34 g) in dry DMF was treated with NaH (1 mmol, 24 mg). Afterstirring at r.t. for 20 min, (2-chloro-ethyl)-diethyl-aminehydrochloride (0.17 g, 1 mmol) and pyridine (0.4 mL) were added. Afterstirring at r.t. for 21 h the reaction mixture was cooled on an ice bathand water was added dropwise. The reaction mixture was neutralised byaddition of aq HCl soln. and extracted with EtOAc. The organic phaseswere combined, washed with brine and dried over MgSO₄. The solvent wasevaporated to dryness. The residue was purified by chromatography, usingEtOAc/MeOH (1:1, v/v) to elute the title compound as light-yellow solid,which was recrystallised from EtOAc/PE. ¹H-NMR (CDCl₃) δ1.00 (t, 6H,J=7.0 Hz, CH₃), 2.59 (m, 2H, CH₂), 2.62 (s, 3H, CH₃), 2.66 (s, 3H, CH₃),2.78 (m, 2H, CH₂), 4.12 (m, 2H, CH₂), 4.72 (s, 2H, CH₂), 6.76 (d, 1H,J=5.5 Hz, pyrimidinyl-H), 7.24 (m, 3H, Ph-H), 7.36 (m, 1H, Ph-H), 7.40(m, 2H, Ph-H), 8.28 (d, 1H, J=5.5 Hz, pyrimidinyl-H). DE MALDI-TOF MS:{M+H}⁺=416.15 (C₂₂H₂₉N₅SO requires 411.56).

Example 21{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine{117}

[0661] A solution of 4-(4-nitro-benzyl)-pyridine (24 mmol, 5.1 g) inMeOH (15 mL) was hydrogenated in the presence of 500 mg palladium (10%on activated carbon). After stirring at r.t. for 20 h the reactionmixture was filtered through Celite 521. The filter aid was washed withMeOH several times. The filtrate was evaporated to dryness to afford4-pyridin-4-ylmethyl-phenylamine (1.84 g) as a grey solid. Anal. RP-HPLCindicated a single product. A solution of this product in MeOH (15 mL)was cooled on an ice bath and was treated first with HCl (conc. 1.75 mL)followed by addition of cyanamide (50% aq soln.; 5 mL). The reactionmixture was heated at reflux for 18 h. The solvent was evaporated andthe residue was washed with EtOAc/MeOH (2:1, v/v) to affordN-(4-pyridin-4-ylmethyl-phenyl)-guanidine hydrochloride (2.25 g) as awhite solid.

[0662] A mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1 mmol, 0.21 g)and N-(4-pyridin-4-ylmethyl-phenyl)-guanidine hydrochloride (2 mmol,0.40 mg) in 2-methoxylethanol was treated with NaOH (40 mg). Thereaction mixture was allowed to heat at reflux for 2 d. The solvent wasevaporated and the residue was crystallised from EtOAc/MeOH to affordthe title compound as an orange solid. ¹H-NMR (300 MHz, d₆-DMSO) δ3.00(s, 3H, CH₃), 3.02 (s, 3H, CH₃), 4.29 (s, 2H, CH₂), 7.44 (d, 1H, J=5.5Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-H), 7.61 (m, 2H, Ar-H), 8.09 (m, 2H,Ph-H), 8.82 (m, 2H, Ar-H), 8.87 (d, 1H, J=5.5 Hz, pyrimidinyl-H). DEMALDI-TOF MS: {M+H}⁺=377.52 (C₂₁H₁₉N₅S requires 373.48).

Example 22{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium{120}

[0663] A mixture of3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.95 mmol, 0.19g) and N-(4-dimethylamino-phenyl)-guanidine (2 mmol) in2-methoxylethanol (5 mL) was added NaOH (40 mg). The reaction mixturewas heated at 120° C. for 18 h. The solvent was evaporated and theresidue was purified by chromatography, using EtOAc/PE to affordN,N-dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine{119} (74 mg) as a reddish-brown solid. ¹H-NMR (300 MHz, d₆-DMSO) δ2.62(s, 3H, CH₃), 2.65 (s, 3H, CH₃), 2.86 (s, 6H, CH₃), 6.73 (m, 2H, Ph-H),6.97 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-I), 8.44 (d, 1H,J=5.0 Hz, pyrimidinyl-H), 9.33 (s, 1H, NH). DE MALDI-TOF MS:{M+H}⁺=329.51 (C₁₇H₁₉N₅S requires 325.43).

[0664] To the above compound (0.13 mmol, 42 mg) in dry acetone (6 mL)was added 12 □L iodomethane dropwise and the reaction mixture was heatedat reflux for 18 h. The solvent was evaporated and the resulting oil wastriturated with toluene (5 mL). The resulting precipitate was filtered,washed with EtOAc and dried under high vacuum overnight to afford thetitle compound (18 mg). ¹H-NMR (300 MHz, d₆-DMSO) δ2.63 (s, 3H, CH₃),2.65 (s, 3H, CH₃), 3.56 (s, 9H, CH₃), 7.17 (d, 1H, J=5.4 Hz,pyrimidinyl-H), 7.88 (m, 2H, Ph-H), 7.96 (m, 2H, Ph-H), 8.57 (d, 1H,J=5.4 Hz, pyrimidinyl-H), 10.04 (s, 1H, NH). DE MALDI-TOF MS:{M+H}=343.39 (C₁₉H₂₅N₅S requires 340.47).

[0665] The biological activity of the compounds of the invention wasdemonstrated by measuring the CDK inhibition by virtue of an assay-basedscreen, and/or by a cytotoxicity assay using one or more cell lines.

Example 23

[0666] Kinase specificity of selected compound

[0667] Selected compounds from the above examples were investigated fortheir kinase selectivity. A panel of protein kinases, including the CDKsrelevant to the present invention, as well as a representative number offunctionally unrelated kinases, were used.

[0668] Assays for CDK4/Cyclin D1, CDK2/Cyclin E, CDIK1/Cyclin B kinasemay be carried out by monitoring phosphorylation of GST-Rb in anappropriate system. Thus, GST-Rb phosphorylation, induced by CDK4/CyclinD1, CDK2/Cyclin E or CDK1/Cyclin B is determined by incorporation ofradio-labeled phosphate in GST-Rb(772-928) using radiolabelled ATP in96-well format in vitro kinase assay. The phosphorylation reactionmixture (total volume 40 μl) consisted of 50 mM HEPES pH 7.4, 20 mMMgCl₂, 5 mM EGTA, 2 mM DTT, 20 mM β-glycerophosphate, 2 mM NaF, 1 mMNa₃VO₄, Protease Inhibitors Cocktail (Sigma, see above), BSA 0.5 mg/ml,1 μg purified enzyme complex, 10 μl of GST-Rb-Sepharose beads, 100 μMATP, 0.2 μCi ³²P-ATP. The reaction is carried out for 30 min at 30° C.at constant shaking. At the end of this period 100 μl of 50 mM HEPES, pH7.4 and 1 mM ATP is added to each well and the total volume transferredonto GFC filtered plate. The plate is washed 5 times with 200 μl of 50mM HEPES, pH 7.4 and 1 mM ATP. To each well were added 50 μl scintillantliquid and the radioactivity of the samples is measured on Scintilationcounter (Topcount, HP). The IC₅₀ values of different peptides werecalculated using GraFit software.

[0669] Alternatively, CDK2/cyclin A kinase assays may be performed in96-well plates using recombinant CDK2/cyclin A. Assay buffer consistedof 25 mM β-glycerophosphate, 20 mM MOPS, 5 mM EGTA, 1 mM DTT, 1 mMNaVO₃, pH 7.4, into which is added 2-4 μg of CDK2/cyclin A withsubstrate pRb(773-928). The reaction is initiated by addition of Mg/ATPmix (15 mM MgCl₂, 100 μM ATP with 30-50 kBq per well of {γ-³²P}-ATP) andmixtures incubated for 10-30 min, as required, at 30° C. Reactions werestopped on ice, followed by filtration through p81 filterplates (WhatmanPolyfiltronics, Kent, UK). After washing 3 times with 75 mMorthophosphoric acid, plates were dried, scintillant added andincorporated radioactivity measured in a scintillation counter(TopCount, Packard Instruments, Pangbourne, Berks, UK).

[0670] PKCα kinase activity may be measured by the incorporation ofradio-labeled phosphate in Histone 3, as described. The reaction mixture(total volume 65 μl) consist of 50 mM Tris-HCl, 1 mM Calcium acetate, 3mM DTT, 0.03 mg/ml Phosphatidylserine, 2.4 μg/ml PMA, 0.04% NP40, 12 mMMg/Cl, purified PKCα-100 ng, Histone 3, 0.2 mg/ml, 100 μM ATP, 0.2 μCi{γ-³²P}-ATP. The reaction is carried over 15 min at 37° C. in microplateshaker and is stopped by adding 10 μl 75 mM orthophosphoric acid andplacing the plate on ice. 50 μl of the reaction mixture is transferredonto P81 filterplate and after washing off the free radioactivephosphate (3 times with 200 μl 75 mM orthophosphoric acid per well) 50μl of scintillation liquid (Microscint 40) were added to each well andthe radioactivity is measured on Scintillation counter (Topcount, HP).

[0671] For use in said assays CDK2 and/or PKC may be obtained fromavailable sources or produced by recombinant methods as described.His-tagged CDK2/Cyclin E and CDK1/Cyclin B may be co-expressed and PKCαsingularly expressed in Sf 9 insect cells infected with the appropriatebaculovirus constructs. The cells are harvested two days after infectionby low speed centrifugation and the proteins purified from the insectcell pellets by Metal-chelate chromatography. Briefly, the insect cellpellet is lysed in Buffer A (10 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.02%NP40 and 5 mM β-marcaptoethanol, 1 mM NaF. 1 mM Na₃VO₄ and ProteaseInhibitors Coctail (Sigma) containing AEBSF, pepstatin A, E 64,bestatin, leupeptin) by sonication. The soluble fraction is cleared bycentrifugation and loaded onto Ni-NTA-Agarose (Quiagen). Non boundproteins were washed off with 300 mM NaCl, 5-15 mM Imidazole in Buffer Aand the bound proteins eluted with 250 mM Imidazole in Buffer A. Thepurified proteins are extensively dialyzed against Storage buffer (20 mMHEPES pH 7.4, 50 mM NaCl, 2 mM DTT, 1 mM EDTA, 1 mM EGTA, 0.02% NP40,10% v/v Glycerol) aliquoted and stored at −70° C. PKC-α—6×His may bepurified the same way but using different buffers—50 mM NaH2PO4, pH 8.0and 0.05% Triton X-100 instead of Tris and NP40 respectively.

[0672] The results in the Table 1 below show that the compounds inquestion exhibit a high degree of selectivity for inhibition of CDKs.TABLE 1 Kinase assay IC₅₀ (μM) CDK1/ CDK4/cyclin Compound cyclin BCDK2/cyclin E D1 ERK-2 PKCa SAPK2a S6 2-[N-(4-Chlorophenyl)]-4- >20  9 ±12 0.5 ± 0.5 >20 >20 >20 >20 (2,4-dimethylthiazol-5-yl)- pyrimidineamine2-N-[(3-Nitrophenyl)-4-(2,4- 0.1 0.17 ± 0.06 0.19 ± 0.14 >20 >20 >20 >20dimethylthiazol-5-yl)- pyrimidineamine 2-[N-(4-Fluorophenyl)]-4- 0.20.019 ± 0.004 0.47 ± 0.14 2.5 >20 >20 1 (2,4-dimethylthiazol-5-yl)-pyrimidineamine

[0673] Further results for CDK2/cyclin E inhibition are shown below inTable 2. TABLE 2 Compound CDK2/cyclin E Compound CDK2/cyclin E  6 5 ± 962 0.06 ± 0.03  7 0.1 63 0.05  9 4.7 72 0.9 12 0.23 ± 0.07 73 0.2 13 8 ±3 74 0.1 20 2.5 ± 0.1 75 0.2 21 0.07 ± 0.08 76 0.8 22 0.02 82 0.2 23 1.783 0.2 28 0.94 ± 0.54 84 0.2 30 0.94 ± 0.49 85 0.09 31 0.2 86 0.13 330.2 87 0.08 35 0.2 ± 0.1 88 0.2 36 0.5 ± 0.2 89 1.2 37 6.4 ± 0.1 90 0.238 0.4 ± 0.3 94 0.6 39 0.22 ± 0.07 97 0.6 40 0.11 ± 0.05 98 1.1 41 0.06102 0.6 45 0.21 ± 0.16 103 1.2 47 0.8 ± 0.4 105 2 48 0.03 106 10 49 0.02107 3 50 0.3 108 0.8 51 0.75 114 1.4 52 0.06 116 0.7 53 0.7 ± 0.4 1180.7 54 0.01 119 1.5 60 4

Example 24

[0674] Anti-proliferative effect of selected compounds

[0675] Selected compounds from the above examples were subjected to astandard cellular proliferation assay using a range of different humantumour cell lines. Standard 72-h MTT (thiazolyl blue;3-{4,5-dimethylthiazol-2-yl}-2,5-diphenyltetrazolium bromide) assayswere performed (Haselsberger, K.; Peterson, D. C.; Thomas, D. G.;Darling, J. L. Anti Cancer Drugs 1996, 7, 331-8; Loveland, B. E.; Johns,T. G.; Mackay, I. R.; Vaillant, F.; Wang, Z. X.; Hertzog, P. J.Biochemistry International 1992, 27, 501-10). Human tumour cell lineswere obtained from the ATCC (American Type Culture Collection, 10801University Boulevard, Manessas, Va. 20110-2209, USA).

[0676] The results in Table 3 below illustrate the anti-proliferativeeffect of compounds described in this application. TABLE 3 72-hCytotoxicity IC₅₀ (μM) Compound A549 Saos-2 MCF-7 AGS DU145 HeLa2-N-[(3-Nitrophenyl)-4-(2,4- 1.5 ± 0.3 1.4 ± 0.3 1.7 ± 0.1 10 ± 0.2 1.0± 0.1 1.2 ± 0.2 dimethylthiazol-5-yl)- pyrimidineamine2-[N-(4-Fluorophenyl)]-4- 5.4 ± 04 8.5 ± 1.6 9.9 ± 0.4 4.2 ± 0.3 4.3 ±0.2 3.2 ± 0.8 (2,4-dimethylthiazol-5-yl)- pyrimidineamine

[0677] Additional data for cytotoxicity assay using the A549 cell lineis shown below in Table 4. TABLE 4 Compound A549 Compound A549  2 41 ±8  60 2.1 ± 0.3  3 5 ± 4 62 1.1 ± 0.2  4 16 ± 11 63 0.8 ± 0.2  7 2.8 6555 ± 50 12 0.2 69 12 ± 5  15 6 70 3 ± 1 21 6.3 72 0.8 ± 0.5 22 20 ± 1 73 9 ± 4 24 5 74 18 ± 4  25 1.5 75 3.2 ± 0.4 26 3.3 76   3 ± 0.9 27 3.882 1.1 ± 0.3 28 3.5 83 0.6 ± 0.3 30  6.4 ± 0.05 84 0.26 ± 0.06 31  0.3 ±0.05 85 0.4 32 23 86 8 ± 6 33 61 ± 55 87 1.7 ± 0.1 34 0.02 88 0.4 ± 0135 4.2 89 18 ± 11 37 25 90 1.8 ± 0.8 38 4.5 ± 1.6 91 22.1 ± 0.2  39 0.392 4.4 ± 3   40 0.3 93 1.1 ± 1   41 0.02 94 0.5 ± 0.6 42 56 95 0.05 ±0.03 45 3.3 ± 0.5 97 4.2 ± 0.4 47 1.8 ± 1.4 98 2.8 ± 2.1 48 6.7 ± 1.1 993.7 ± 2.7 49  2.2 ± 0.02 101 0.9 ± 0.2 50 8.8 ± 10  102 0.8 ± 0.2 51 0.3± 0.3 104 4.9 ± 2.5 52 0.8 ± 0.3 105 0.7 ± 0.9 53 12 ± 5  106 2.8 ± 0.557 5.2 ± 0.4 107 0.7 ± 0.2 59 22 ± 21

[0678] The following examples indicate the ability of some compounds toinduce cell cycle arrest and apoptosis in human tumour cells.

Example 25

[0679] Induction of mitotic arrest and apoptosis in human tumour cells

[0680] Human osteosarcoma tumour cells (Saos-2) were treated with 1 μMof compound 28 for 48 h. The accumulation of mitotic cells andappearance of apoptotic cells was observed by phase-contract microscopy(FIG. 1). Compound 28-induced accumulation of mitotic cells was furtherquantified using mitotic index HitKit (Cellomix).

Example 26

[0681] The effect of compound 28 on the mitotic index was studied usingmitotic index HitKit (Cellomix). Vinblastine was used as control in theexperiments. Plates of A549 cells were prepared as instructed in themitotic index HitKit and the results obtained are shown in the FIGS. 3and 4.

Example 27

[0682]FIG. 5 shows the effect of compound 28 on the mitotic index. Thedata shown in FIG. 5 demonstrate the effects of the compounds tested onthe percentage of mitotic cells observed in 6 fields within each well.Compound 28 increased the percentage of mitotic cells from 2.6% (datanot shown) in untreated wells to a maximum of 17% at a concentration of4.4 μM. Above this concentration a decrease in the number of mitoticcells is observed which correlates with a decrease in the total numberof cells. This indicates that toxicity is occurring and that cells aredetaching from the bottom of the plate. Vinblastine increases thepercentage of mitotic cells to a maximum of 31% at a concentration of 22nM with toxicity being seen again above this concentration.

Example 28

[0683] In addition to the induction of apoptosis some of the compoundsof the invention are capable of inducing forms of programmed cell deaththat is distinct from apoptosis by the criteria of morphology. Theinduction of programmed cell death by compound 28, characterised bycytoplasmic vaculation, is shown in FIG. 6. Human lung carcinoma cells(A549) were treated for 16 h with 10 μM compound 28. Extensivecytoplasmic vaculation is observed in the treated cell (A) but not inthe control cells (B).

What is claimed is:
 1. A compound of general formula I:

wherein X¹ is CH and X² is S; or one of X¹ and X² is S, and the other ofX¹ and X² is N; Z is NH, NHCO, NHSO₂, NHCH₂, CH₂, CH₂CH₂, or CH═CH; R¹,R², and R³ are independently H, alkyl, aryl, aralkyl, heterocycle,halogen, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NH—R′, N—(R′)(R″), NH—COR′,NH-aryl, N-(aryl)₂, COOH, COO—R′, COO-aryl, CONH₂, CONH—R′,CON—(R′)(R″), CONH-aryl, CON-(aryl)₂, SO₃H, SO₂NH₂, CF₃, CO—R′, orCO-aryl, wherein alkyl, aryl, aralkyl, heterocycle and NH-aryl groupsmay be further substituted with one or more groups selected fromhalogen, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃; at least oneof the groups R¹ and R² being other than H when either X¹ or X² is S;R⁴, R⁵, R⁶, R⁷, and R⁸ are independently from each other H, substitutedor unsubstituted lower alkyl, halogen, amino, carbamoyl, sulfamyl, NO₂,CN, OH, substituted or unsubstituted alkoxy, NH₂, NH—R′, alkyl-aryl,alkyl-heteroaryl, NH(C═NH)NH₂, N(R′)₃ ⁺, N—(R′)(R″), COOH, COO—R′,CONH₂, CONH—R′, CON—(R′) (R″), SO₃H, SO₂NH₂, CF₃ or(CH₂)_(n)O(CH₂)_(m)NR′R″, (CH₂)_(n)CO₂(CH₂)_(m)OR′″ wherein n is 0, 1, 2or 3 and m is 1, 2 or 3; wherein R′, R″ and R′″ are each independentlyalkyl groups that may be the same or different; and pharmaceuticallyacceptable salts thereof.
 2. A compound according to claim 1, wherein X¹and X² are S and N respectively, or CH and S respectively; R¹, R² and R³are each independently selected from the group consisting of: H, alkyl,aryl, aralkyl, halogen, NO₂, CN, OH, alkoxy, aryloxy, NH₂, NHCOR′,NHCOR′, NH-aryl, NH—R′, N—(R′)(R″), COOH, COO—R′, CONH₂, CONH—R′,CON—(R′)(R″), SO₃H, SO₂NH₂, CF₃, and CO—R′ wherein alkyl, aryl, NH-aryland aralkyl groups may be further substituted with one or more groupsselected from halogen, NO₂, CN, OH, O-methyl, NH₂, COOH, CONH₂ and CF₃;Z is selected from the group consisting of: NH, NHSO₂ and NHCH₂; R⁴, R⁵,R⁶, R⁷, and R⁸ are each independently selected from the group consistingof: H, OH, halogen, nitro, amino, alkoxy, carbamoyl, sulfamyl, C₁₋₄alkyl, substituted C₁₋₄ alkyl, COOH, COOR′, CN, CF₃,(CH₂)_(n)O(CH₂)_(m)NR′R″, alkyl-aryl, alkyl-heteroaryl, NH(C═NH)NH₂,N(R′)₃ ⁻, N(R′)(R″) and (CH₂)_(n)CO₂(CH₂)_(m)OR′″.
 3. A compoundaccording to claim 1, wherein X¹ and X² are S and N respectively.
 4. Acompound according to claim 1, 2, or 3, wherein Z is NH and R³ is H. 5.A compound according to claim 1, 2, or 3, wherein R¹ and R² are eachindependently one or more of halogen, a C₁₋₄ alkyl group, H, aryl,heterocycle or NH(R′).
 6. A compound according to claim 5, wherein R¹and R² are chloro or methyl.
 7. A compound according to claim 1, 2, or3, wherein R³ is selected from the group consisting of: H, aryl,substituted aryl, halogen, C₁₋₄ alkoxy and OH.
 8. A compound accordingto claim 1, 2, or 3, wherein R⁴, R⁵, R⁶, R⁷, and R⁸ are selectedindependently from the group consisting of: F, NH₂, NO₂, OH, Cl, Br, I,CF₃, OMe, COOH, COOR′, CN, H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂CO₂CH₂CH₂OMe,NH(C═NH)NH₂, and CO₂CH₂CH₂OMe, CH₂OCH₂CH₂NEt₂, CH₂-heteroaryl, NMe₃ ⁺,NMe₂.
 9. A compound according to claim 1 selected from the groupconsisting of: (a)2-{N-(phenyl)}-4-(2,4-dimethylthiazol-5-yl)pyrimidineamines in which thephenyl group is 2-, 3- or 4-substituted by at least one of Me, F, NH₂,NO₂, OH, Cl, Br, I, CF₃, OMe, CN, COOH, CH₂OH, COOMe, COOEt,NH(C═NH)NH₂, CH₂CO₂CH₂CH₂OMe, CH₂-pyridyl, CH₂OCH₂CH₂NEt₂, CO₂CH₂CH₂OMe,NMe₃ ⁺ and NMe₂; (b)2-{N-(phenyl)}-4-(2,5-dichloro-thien-3-yl)pyrimidineamines in which thephenyl group is 2-, 3- or 4-substituted by at least one of F, NO₂, OH,Cl, or OMe; (c)2-{N-(phenyl)}-4-(2,5-dimethyl-thien-3-yl)pyrimidineamines in which thephenyl group is 2-, 3- or 4-substituted by at least one of F, NO₂, OH,Cl, or OMe; and (d)2-{N-(phenyl)}-4-(4-methyl-2-methylamino-thiazol-5-yl)pyrimidineaminesin which the phenyl group is 2-, 3- or 4-substituted by at least one ofF, OH, I, NO₂, Cl, COOR′, Br, OMe or CF₃.
 10. A compound according toclaim 9, wherein for group (a) the phenyl group is mono-substituted byF, NH₂, NO₂, OH, Cl, Br, I, CF₃, OMe, CN, CH₂OH, COOH, COOMe, COOEt,CH₂CO₂CH₂CH₂OMe or CO₂CH₂CH₂OMe at any of the 2, 3 or 4-positions, ordi-substituted by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro,2,4-dichloro, 3,5-dichloro, 3,4-dichloro, 4-hydroxy-2-nitro,4-hydroxy-3-nitro, 6-chloro-3-carboxy, 4-chloro-3-carboxy,6-chloro-2-carboxy, 2-fluoro-4-iodo, 2-hydroxy-4-methoxy,3-chloro-4-iodo, 3-chloro-4-hydroxy, 3-chloro-4-methyl,3-chloro-4-methoxy, 4-fluoro-3-nitro, 6-chloro-3-methoxycarbonyl,3-chloro-4-methoxcarbonyl, 3-chloro-4-ethoxcarbonyl,2-hydroxy-4-methoxy, 2-chloro-5-methoxycarbonyl,4-chloro-3-methoxycarbonyl, 6-chloro-3-(CO₂CH₂CH₂OMe),3-chloro-4-(CO₂CH₂CH₂OMe), 4-chloro-3-trifluoromethyl, or3-(CO₂CH₂CH₂OMe)-4-fluoro; for group (b) the phenyl group ismono-substituted by chloro, or, nitro, at any of the 2, 3 or4-positions; for group (c) the phenyl group is mono-substituted bychloro at any of the 2, 3 or 4-positions; and for group (d) the phenylgroup is mono-substituted by chloro, bromo, iodo, fluoro, OH, nitro, CF₃or OMe at any of the 2, 3 or 4 positions, or disubstituted by4-hydroxy-3-nitro, 3-chloro-4-ethoxycarbonyl, 3,4-difluoro,2,4-difluoro, 4-chloro-3-trifluoromethyl or 4-fluoro-3-nitro.
 11. Acompound according to claim 9 wherein for group (a) the phenyl group ismonosubstituted by Br, I or CF₃.
 12. A compound according to claim 1selected from the group consisting of4-(2,5-Dichloro-thiophen-3-yl)-2-phenyl-pyrimidine,(2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(2-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,(4-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,(2-Chloro-phenyl) {4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,(2-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-pyridin-2-yl-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine,(3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,4-Chloro-N-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzenesulfonamide,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-fluoro-benzenesulfonamide,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-4-nitro-benzenesulfonamide,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acidmethyl ester,(3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acid,{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-ylamino}-phenol,(3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino}-2-nitro-phenol,(4-Fluoro-phenyl)-{4-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol,{4-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,(4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{2-Amino-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,{4-(4Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,3-{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,acid ethyl ester,2-Chloro-4-{4-(2-ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid 2-methoxy-ethyl ester,4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid, 2-Chloro-5-{3-(2,4-dimethyl-thiazol-5-yl)-phenylamino}-benzoicacid,{4-(2-Allylamino-4-methylthiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,(4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3trifluoromethyl-phenyl)-amine,{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,(3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,2-Chloro-4-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,(3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Fluoro-3-nitro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-{2-(4-Nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-ylamino}-phenol,N-{5-{2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl}-4-methyl-thiazol-2-yl}-acetamide,(4-Fluoro-phenyl)-{4-{2-(4-nitro-phenylamino)-thiazol-5-yl}-pyrimidin-2-yl}-amine,4-{4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-methanol,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,{3-(2-Diethylamino-ethoxymethyl)-phenyl}-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,and{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.13. A compound according to claim 1 selected from the group consistingof:(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,5-Dichloro-thiophen-3-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-nitro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(2,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,5-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,(3-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-iodo-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine,(3,4-Difluoro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-methoxy-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-methoxy-phenyl)-amine,3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzonitrile,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acidmethyl ester,(3-Chloro-4-methyl-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-4-methoxy-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoic acid,{4-Bromo-6-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,4-{4-(4-Methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,(4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,(4-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-2-nitro-phenol,2-Chloro-4-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,{4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine,(3-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2-Allylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,3-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,(4-Bromo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,5-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-2-fluoro-benzoicacid 2-methoxy-ethyl ester,2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,(3,5-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-3-trifluoromethyl-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Methoxy-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,2-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-5-methoxy-phenol,(3-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,(3,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,N-{3-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-guanidine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-pyridin-4-ylmethyl-phenyl)-amine,N,N-Dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine,and{4-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-phenyl}-trimethyl-ammonium.14. A compound according to claim 1 selected from the following:{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine,(4-Bromo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-{4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino}-phenol,and(4-Fluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.15. A compound according to claim 1 selected from the group consistingof:(2-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(3-Chloro-phenyl)-{4-(2,5-dichloro-thiophen-3-yl)-pyrimidin-2-yl}-amine,(2-Chloro-phenyl)-{4-(2,5-dimethyl-thiophen-3-yl)-pyrimidin-2-yl}-amine,(3,5-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(2,4-Dichloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-trifluoromethyl-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-trifluoromethyl-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-iodo-phenyl)-amine,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine,N-{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-3-nitro-benzenesulfonamide,{4-(2,4-Dimethyl-thiazol-5-yl)-6-phenyl-pyrimidin-2-yl}-(3-nitro-phenyl)-amine,(3,4-Difluoro-phenyl)-{4-(4-methyl-2-phenyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,(4-Chloro-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl}-amine,4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-2,6-dimethoxy-phenol,4-{6-(2,4-Dimethyl-thiazol-5-yl)-2-(4-fluoro-phenylamino)-pyrimidin-4-yl}-phenol,2-Chloro-5-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,3-Chloro-2-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid ethyl ester,{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(2-fluoro-4-iodo-phenyl)-amine,(3-Chloro-4-iodo-phenyl)-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-amine,4-Chloro-3-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino}-benzoicacid methyl ester,(3-Iodo-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine,and(2,4-Difluoro-phenyl)-{4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl}-amine.16. The compound of claim 1 that is{4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(4-iodo-phenyl)-amine.17. Pharmaceutical compositions comprising a compound as defined inclaims 1, 2, or 3 or a pharmaceutically acceptable salt thereof togetherwith a pharmaceutically acceptable excipient.
 18. Pharmaceuticalcompositions according to claim 17 which further comprise one or moreother anticancer agents.
 19. A method of treating a proliferativedisorder in a subject, comprising administering to the subject one ormore compounds of claims 1, 2, or 3 or pharmaceutically acceptable saltsthereof to the subject, thereby treating the proliferative disorder inthe subject.
 20. The method of claim 19, wherein the proliferativedisorder is cancer or leukemia.
 21. The method of claim 19, wherein saidone or more compounds are administered in an amount sufficient toinhibit at least one CDK enzyme.
 22. The method of claim 21, wherein theCDK enzyme is CDK2 or CDK4.
 23. The method of 19, wherein said compoundis administered in combination with one or more other anticancercompounds.
 24. The method of claim 20, wherein said one or morecompounds are administered in an amount sufficient to inhibit at leastone CDK enzyme.
 25. The method of claim 24, wherein the CDK enzyme isCDK2 or CDK4.
 26. The method of 20, wherein said compound isadministered in combination with one or more other anticancer compounds.27. The method of 21, wherein said compound is administered incombination with one or more other anticancer compounds.
 28. The methodof 22, wherein said compound is administered in combination with one ormore other anticancer compounds.